Non-imidazole heterocyclic compounds

ABSTRACT

Certain non-imidazole heterocyclic compounds are histamine H 3  modulators useful in the treatment of histamine H 3  receptor mediated diseases.

FIELD OF THE INVENTION

The present invention relates to a series of 5- and 6-memberednitrogen-containing heterocycles, their synthesis and their use, forexample, for the treatment of disorders and conditions mediated by thehistamine H₃ receptor.

BACKGROUND OF THE INVENTION

Histamine {2-(imidazol-4-yl)ethylamine} is a transmitter substance.Histamine exerts a physiological effect via multiple distinct G-proteincoupled receptors. It plays a role in immediate hypersensitivityreactions and is released from mast cells following antigen IgE antibodyinteraction. The actions of released histamine on the vasculature andsmooth muscle system account for the symptoms of the allergic response.These actions occur at the H₁ receptor (Ash, A. S. F. and Schild, H. O.,Br. J. Pharmac. Chemother. 1966, 27:427-439) and are blocked by theclassical antihistamines (e.g. diphenhydramine). Histamine is also animportant regulator of gastric acid secretion through its action onparietal cells. These effects of histamine are mediated via the H₂receptor (Black, J. W. et al., Nature 1972, 236:385-390) and are blockedby H₂ receptor antagonists (e.g. cimetidine). The third histaminereceptor —H₃— was first described as a presynaptic autoreceptor in thecentral nervous system (CNS) (Arrang, J.-M. et al., Nature 1983,302:832-837) controlling the synthesis and release of histamine. Recentevidence has emerged showing that H₃ receptors are also locatedpresynaptically as heteroreceptors on serotonergic, noradrenergic,dopaminergic, cholinergic, and GABAergic (gamma-aminobutyric acidcontaining) neurons. These H₃ receptors have also recently beenidentified in peripheral tissues such as vascular smooth muscle.Consequently, there are many potential therapeutic applications forhistamine H₃ agonists, antagonists, and inverse agonists. (See: “TheHistamine H₃ Receptor-A Target for New Drugs”, Leurs, R., and Timmerman,H., (Eds.), Elsevier, 1998; Morisset, S. et al., Nature 2000,408:860-864.) A fourth histamine receptor —H₄— was recently described byOda, T. et al. (J. Biol. Chem. 2000, 275(47):36781-36786).

The potential use of histamine H₃ agonists in sleep/wake andarousal/vigilance disorders is suggested based on animal studies (Lin,J.-S. et al., Brain Res. 1990, 523:325-330; Monti, J. M. et al., Eur. J.Pharmacol. 1991, 205:283-287). Their use in the treatment of migrainehas also been suggested (McLeod, R. L. et al., Soc. Neurosci. Abstr.1996, 22:2010) based on their ability to inhibit neurogenicinflammation. Other applications could include a protective role inmyocardial ischemia and hypertension where blockade of norepinephrinerelease is beneficial (Imamura, M. et al., J. Pharmacol. Exp. Ther.1994, 271(3):1259-1266). It has been suggested that histamine H₃agonists may be beneficial in asthma due to their ability to reducenon-adrenergic non-cholinergic (NANC) neurotransmission in airways andto reduce microvascular leakage (Ichinose, M. and Barnes, P. J., Eur. J.Pharmacol. 1989, 174:49-55).

Several indications for histamine H₃ antagonists and inverse agonistshave similarly been proposed based on animal pharmacology experimentswith known histamine H₃ antagonists (e.g. thioperamide). These includedementia, Alzheimer's disease (Panula, P. et al., Soc. Neurosci. Abstr.1995, 21:1977), epilepsy (Yokoyama, H. et al., Eur. J. Pharmacol. 1993,234:129-133), narcolepsy, with or without associated cataplexy,cataplexy, disorders of sleep/wake homeostasis, idiopathic somnolence,excessive daytime sleepiness (EDS), circadian rhythm disorders,sleep/fatigue disorders, fatigue, drowsiness associated with sleepapnea, sleep impairment due to perimenopausal hormonal shifts, jet lag,Parkinson's-related fatigue, multiple sclerosis (MS)-related fatigue,depression-related fatigue, chemotherapy-induced fatigue, eatingdisorders (Machidori, H. et al., Brain Res. 1992, 590:180-186), motionsickness, vertigo, attention deficit hyperactivity disorders (ADHD),learning and memory (Barnes, J. C. et al., Soc. Neurosci. Abstr. 1993,19:1813), and schizophrenia (Schlicker, E. and Marr, I.,Naunyn-Schmiedeberg's Arch. Pharmacol. 1996, 353:290-294). (Also see:Stark, H. et al., Drugs Future 1996, 21(5):507-520; and Leurs, R. etal., Prog. Drug Res. 1995, 45:107-165 and references cited therein.)Histamine H₃ antagonists, alone or in combination with a histamine H₁antagonist, are reported to be useful for the treatment of upper airwayallergic response (U.S. Pat. Nos. 5,217,986; 5,352,707 and 5,869,479).Recently, a histamine H₃ antagonist (GT-2331) was identified and isbeing developed by Gliatech Inc. (Gliatech Inc. Press Release Nov. 5,1998; Bioworld Today, Mar. 2, 1999) for the treatment of CNS disorders.

As noted, the literature related to histamine H₃ ligands has beencomprehensively reviewed (“The Histamine H₃ Receptor—A Target for NewDrugs”, Leurs, R. and Timmerman, H., (Eds.), Elsevier, 1998). Withinthis reference the medicinal chemistry of histamine H₃ agonists andantagonists was reviewed (see Krause, M. et al., and Phillips, J. G. andAli, S. M., respectively). The importance of an imidazole moietycontaining only a single substitution in the 4-position was noted,together with the deleterious effects of additional substitution onactivity. Particularly, methylation of the imidazole ring at any of theremaining unsubstituted positions was reported to strongly decreaseactivity. Additional publications support the hypothesis that animidazole function is essential for high affinity histamine H₃ receptorligands (see Ali, S. M. et al., J. Med. Chem. 1999, 42:903-909, andStark, H. et al., and references cited therein). However, manyimidazole-containing compounds are substrates for histamine methyltransferase, the major histamine metabolizing enzyme in humans, whichleads to shortened half-lives and lower bioavailability (see Rouleau, A.et al., J. Pharmacol. Exp. Ther. 1997, 281(3):1085-1094). In addition,imidazole-containing drugs, via their interaction with the cytochromeP₄₅₀ monooxygenase system, can participate in unfavorablebiotransformations due to enzyme induction or enzyme inhibition (see:Kapetanovic, I. M. and Kupferberg, H. J., Drug Metab. Dispos. 1984,12(5):560-564; Sheets, J. J. and Mason, J. I., Drug Metab. Dispos. 1984,12(5):603-606; Back, D. J. and Tjia, J. F., Br. J. Pharmacol. 1985,85:121-126; Lavrijsen, K. et al., Biochem. Pharmacol. 1986,35(11):1867-1878; Albengres, E. et al., Drug Safety 1998, 18(2):83-97).The poor blood brain barrier penetration of earlier histamine H₃receptor ligands may also be associated with the imidazole fragment(Ganellin, C. R. et al., Arch. Pharm. Pharm. Med. Chem. (Weinheim, Ger.)1998, 331:395-404).

More recently, several publications have described histamine H₃ ligandsthat do not contain an imidazole moiety, for example: Ganellin, C. R. etal.; Walczynski, K. et al., Arch. Pharm. Pharm. Med. Chem. (Weinheim,Ger.) 1999, 332:389-398; Walczynski, K. et al., Farmaco 1999,54:684-694; Linney, I. D. et al., J. Med. Chem. 2000, 43:2362-2370;Tozer, M. J. and Kalindjian, S. B., Exp. Opin. Ther. Patents 2000,10:1045-1055; U.S. Pat. No. 5,352,707; PCT Application WO 99/42458, Aug.26, 1999; PCT Application WO 02/076925; and European Patent Application0978512, Feb. 9, 2000.

In addition, a more recent review of this topic was presented (Tozer, M.T. and Kalindjian, S. B. Exp. Opin. Ther. Patents 2000, 10:1045).Additional publications and patents, concerning both histamine H₃agonists and antagonists, have appeared since the publication of theLeurs monograph. Most noteworthy is the development of non-imidazolehistamine H₃ antagonists (Apodaca et al WO 02/12214; Apodaca et al WO02/12190; Bogenstaetter et al 02/12224; Carruthers et al WO 01/74810;Chai et al WO 01/74814; Breitenbucher et al WO 01/74815; Breitenbucheret al WO 01/74813; Breitenbucher et al WO 01/74773; Bennani et al WO02/06223; Bennani et al WO 01/66534; Schwartz et al EP 0978512 A1;Schwartz et al WO 00/06254; Linney et al J. Med. Chem. 2000, 43, 2362;and Ganellin et al Arch. Pharm. Pharm. Med. Chem. 1998, 331, 395).

The compounds of the present invention do not contain the imidazolemoiety, and its inherent liabilities, and yet maintain potency at thehuman H₃ receptor as determined by receptor binding to the humanhistamine H₃ receptor (see Lovenberg, T. W. et al., Mol. Pharmacol.1999, 55:1101-1107). Screening using the human receptor is particularlyimportant for the identification of new therapies for the treatment ofhuman disease. Conventional binding assays, for example, are determinedusing rat synaptosomes (Garbarg, M. et al., J. Pharmacol. Exp. Ther.1992, 263(1):304-310), rat cortical membranes (West, R. E. et al., Mol.Pharmacol. 1990, 38:610-613), and guinea pig brain (Korte, A. et al.,Biochem. Biophys. Res. Commun. 1990, 168(3):979-986). Only limitedstudies have been performed previously using human tissue but theseallude to significant differences in the pharmacology of rodent andprimate receptors (West, R. E. et al., Eur. J. Pharmacol. 1999,377:233-239).

Described herein is a series of 5- and 6-membered aromaticnitrogen-containing heterocyclic compounds with the ability to modulatethe activity of the histamine receptor, specifically the H₃ receptor,without the inherent problems associated with the presence of animidazole moiety.

SUMMARY OF THE INVENTION

The invention features a heterocyclic compound of formula (I):

wherein

-   in the A- and B-containing ring,

I) A, B¹ and B² are CH;

II) A is CH, one of B¹ and B² is N, and the other of B¹ and B² is CH; or

III) A is absent, B¹ is CH, and B² is O;

-   L is —C₁₋₄alkylene- or a covalent bond;-   Q is —(CH₂)_(m)O—, —(CH₂)_(n)C═C— (where the —O— and —C═C— portions    are directly attached to the ring), carbonyl, or thiocarbonyl;-   m is 2, 3, or 4;-   n is 1, 2, 3, or 4;-   R¹, optionally mono- or di-substituted with R^(p), is independently    selected from the group consisting of —H, —C₁₋₇alkyl, —C₂₋₇alkenyl,    —C₂₋₇alkynyl, —C₃₋₇cycloalkyl, phenyl, benzyl, pyridinyl,    pyrimidinyl, furanyl, thienyl, pyrrolyl, and a 5-, 6-, or 7-membered    monocyclic non-aromatic heterocyclic ring having 1 or 2 heteroatom    members selected from O, S, —N═, >NH, and >NC₁₋₄alkyl, having 0, 1,    or 2 double bonds;-   R², optionally mono- or di-substituted with R^(p), is independently    selected from the group consisting of —C₁₋₇alkyl, —C₂₋₇alkenyl,    —C₂₋₇alkynyl, —C₃₋₇cycloalkyl, phenyl, benzyl, pyridinyl,    pyrimidinyl, furanyl, thienyl, pyrrolyl, and a 5-, 6-, or 7-membered    monocyclic non-aromatic heterocyclic ring having 1 or 2 heteroatom    members selected from O, S, —N═, >NH, and >NC₁₋₄alkyl, having 0, 1,    or 2 double bonds;    or, alternatively,-   R¹ and R² may be taken together with the nitrogen of attachment to    form a ring, said ring selected from the group consisting of:    -   i) a 4-7 membered non-aromatic heterocyclic ring, said        heterocyclic ring having 0 or 1 additional heteroatom members        separated from the nitrogen of attachment by at least one carbon        member and selected from O, S, —N═, >NH, and >NC₁₋₄alkyl, having        0, 1, or 2 double bonds, having 0, 1, or 2 carbon members which        is a carbonyl, having 0, 1, or 2 substituents R^(q); and    -   ii) a benzo or pyrido fused 4-7 membered non-aromatic        heterocyclic ring, said heterocyclic ring having 0 or 1        additional heteroatom members separated from the nitrogen of        attachment by at least one carbon member and selected from O, S,        —N═, >NH, and >NC₁₋₄alkyl, having 0 or 1 additional double        bonds, having 0, 1, or 2 carbon members which is a carbonyl, and        having 0, 1, or 2 substituents R^(q);    -   R^(p) is independently selected from the group consisting of        —C₁₋₆alkyl, —C₂₋₆alkenyl, —C₃₋₆cycloalkyl, phenyl, pyridyl,        furanyl, thienyl, benzyl, pyrimidinyl, pyrrolyl, halo, —OH,        —OC₁₋₆alkyl, —OC₃₋₆cycloalkyl, —Ophenyl, —Obenzyl, —SH,        —SC₁₋₆alkyl, —SC₃₋₆cycloalkyl, —Sphenyl, —Sbenzyl, —CN, —NO₂,        —N(R^(y))R^(z) (wherein R^(y) and R^(z) are independently        selected from H and C₁₋₄alkyl; or R^(y) and R^(z) may be taken        together with the nitrogen of attachment to form a 5-, 6-, or        7-membered monocyclic heterocyclic ring having 1 or 2 additional        heteroatom members selected from O, S, —N═, >NH, and        >NC₁₋₄alkyl, said ring optionally substituted with —C₁₋₄alkyl,        —OH, —OC₁₋₄alkyl, halo, or —COOC₁₋₄alkyl), —(C═O)N(R^(y))R^(z),        —(C═O)C₁₋₄alkyl, —SCF₃, —OCF₃, —CF₃, and —COOC₁₋₄alkyl, and        —COOH;    -   R^(q) is independently selected from the group consisting of        —C₁₋₆alkyl, halo, —OH, —OC₁₋₆alkyl, —CN, —NO₂, —CF₃, and        —COOC₁₋₄alkyl,-   R³, optionally mono- or di-substituted with R^(s), is independently    selected from the group consisting of —H, —C₁₋₇alkyl, —C₂₋₇alkenyl,    —C₂₋₇alkynyl, —C₃₋₇cycloalkyl, phenyl, benzyl, pyridinyl,    pyrimidinyl, furanyl, thienyl, pyrrolyl, and a 5-, 6-, or 7-membered    monocyclic non-aromatic heterocyclic ring having 1 or 2 heteroatom    members selected from O, S, —N═, >NH, and >NC₁₋₄alkyl, having 0, 1,    or 2 double bonds; and-   R⁴, optionally mono- or di-substituted with R^(s), is independently    selected from the group consisting of —C₁₋₇alkyl, —C₂₋₇alkenyl,    —C₂₋₇alkynyl, —C₃₋₇cycloalkyl, phenyl, benzyl, pyridinyl,    pyrimidinyl, furanyl, thienyl, pyrrolyl, and a 5-, 6-, or 7-membered    monocyclic non-aromatic heterocyclic ring having 1 or 2 heteroatom    members selected from O, S, —N═, >NH, and >NC₁₋₄alkyl, having 0, 1,    or 2 double bonds;    -   R^(s) is independently selected from the group consisting of        —C₁₋₆alkyl, —C₂₋₆alkenyl, —C₃₋₆cycloalkyl, phenyl, pyridyl,        furanyl, thienyl, benzyl, pyrimidinyl, pyrrolyl, halo, —OH,        —OC₁₋₆alkyl, —OC₃₋₆cycloalkyl, —Ophenyl, —Obenzyl, —SH,        —SC₁₋₆alkyl, —SC₃₋₆cycloalkyl, —Sphenyl, —Sbenzyl, —CN, —NO₂,        —N(R^(y))R^(z) (wherein R^(y) and R^(z) are independently        selected from H and C₁₋₄alkyl; or R^(y) and R^(z) may be taken        together with the nitrogen of attachment to form a 5-, 6-, or        7-membered monocyclic heterocyclic ring having 1 or 2 additional        heteroatom members selected from O, S, —N═, >NH, and        >NC₁₋₄alkyl, said ring optionally substituted with —C₁₋₄alkyl,        —OH, —OC₁₋₄alkyl, halo, or —COOC₁₋₄alkyl), —(C═O)N(R^(y))R^(z),        —(C═O)C₁₋₄alkyl, —SCF₃, —OCF₃, —CF₃, —COOC₁₋₄alkyl, and —COOH;        or, alternatively-   R³ and R⁴ may be taken together with the nitrogen of attachment to    form a ring, said ring selected from the group consisting of:    -   i) a 4-7 membered non-aromatic heterocyclic ring said        heterocyclic ring having 0 or 1 additional heteroatom members        separated from the nitrogen of attachment by at least one carbon        member and selected from O, S, —N═, >NH, and >NC₁₋₄alkyl, having        0, 1, or 2 double bonds, having 0, 1, or 2 carbon members which        is a carbonyl, having 0, 1, or 2 substituents R^(t); and    -   ii) a benzo or pyrido fused 4-7 membered non-aromatic        heterocyclic ring said heterocyclic ring having 0 or 1        additional heteroatom members separated from the nitrogen of        attachment by at least one carbon member and selected from O, S,        —N═, >NH, and >NC₁₋₄alkyl, having 0 or 1 additional double        bonds, having 0, 1, or 2 carbon members which is a carbonyl, and        having 0, 1, or 2 substituents R^(t);    -   R^(t) is independently selected from the group consisting of is        independently selected from the group consisting of —C₁₋₆alkyl,        halo, —OH, —OC₁₋₆alkyl, —CN, —NO₂, —CF₃, and —COOC₁₋₄alkyl;-   and enantiomers, diastereomers, hydrates, solvates and    pharmaceutically acceptable salts, esters and amides thereof.

Similarly, isomeric forms of the compounds of formula (I), and of theirpharmaceutically acceptable salts, esters, and amides, are encompassedwithin the present invention, and reference herein to one of suchisomeric forms is meant to refer to at least one of such isomeric forms.One of ordinary skill in the art will recognize that compounds accordingto this invention may exist, for example in a single isomeric formwhereas other compounds may exist in the form of a regioisomericmixture.

The invention also features pharmaceutical compositions containing suchcompounds and methods of using such compositions in the treatment orprevention of disease states mediated by histamine H₃ receptor activity.

The invention also features a pharmaceutical composition comprising acompound of the invention and a pharmaceutically acceptable carrier; andmethods of preparing or formulating such compositions. A composition ofthe invention may further include more than one compound of theinvention, or a combination therapy (combination formulation orcombination of differently formulated active agents).

The invention also provides methods of treating certain conditions anddiseases, each of which methods includes administering a therapeuticallyeffective (or jointly effective) amount of a compound or composition ofthe invention to a subject in need of such treatment. The disclosedcompounds are useful in methods for treating or preventing neurologicdisorders including sleep/wake and arousal/vigilance disorders (e.g.insomnia and jet lag), attention deficit hyperactivity disorders (ADHD),learning and memory disorders, cognitive dysfunction, migraine,neurogenic inflammation, dementia, mild cognitive impairment(pre-dementia), Alzheimer's disease, epilepsy, narcolepsy with orwithout associated cataplexy, cataplexy, disorders of sleep/wakehomeostasis, idiopathic somnolence, excessive daytime sleepiness (EDS),circadian rhythm disorders, sleep/fatigue disorders, fatigue, drowsinessassociated with sleep apnea, sleep impairment due to perimenopausalhormonal shifts, Parkinson's-related fatigue, MS-related fatigue,depression-related fatigue, chemotherapy-induced fatigue, eatingdisorders, obesity, motion sickness, vertigo, schizophrenia, substanceabuse, bipolar disorders, manic disorders and depression, as well asother histamine H₃ receptor mediated disorders such as upper airwayallergic response, asthma, itch, nasal congestion and allergic rhinitisin a subject in need thereof. For example, the invention featuresmethods for preventing, inhibiting the progression of, or treating upperairway allergic response, asthma, itch, nasal congestion and allergicrhinitis.

In yet another embodiment, the disclosed compounds may be used in acombination therapy method including administering a jointly effectivedose of an H₃ antagonist and administering a jointly effective dose of ahistamine H₁ antagonist, such as loratidine (CLARITIN™), desloratidine(CLARINEX™), fexofenadine (ALLEGRA™) and cetirizine (ZYRTEC™), for thetreatment of allergic rhinitis, nasal congestion, and allergiccongestion.

In yet another embodiment, the disclosed compounds may be used in acombination therapy method, including administering a jointly effectivedose of an H₃ antagonist and administering a jointly effective dose of aneurotransmitter re-uptake blocker, such as a selective serotoninre-uptake inhibitor (SSRI), a serotonin-norepinephrine reuptakeinhibitor, a noradrenergic reuptake inhibitor, or a non-selectiveserotonin, dopamine or norepinephrine re-uptake inhibitor, includingfluoxetine (PROZAC™), sertraline (ZOLOFT™), paroxetine (PAXIL™) andamitryptyline, for the treatment of depression, mood disorders orschizophrenia. In an alternative embodiment, the disclosed compounds maybe used in a combination therapy method, including administering ajointly effective dose of an H₃ antagonist and administering a jointlyeffective dose of modafinil, for example, for the treatment ofnarcolepsy, excessive daytime sleepiness (EDS), Alzheimer's disease,depression, attention deficit disorders, MS-related fatigue,post-anesthesia grogginess, cognitive impairment, schizophrenia,spasticity associated with cerebral palsy, age-related memory decline,idiopathic somnolence, or jet-lag.

Additional features and advantages of the invention will become apparentfrom the detailed description and examples below, and the appendedclaims.

DETAILED DESCRIPTION

-   Preferably, the A- and B-containing ring is selected from the group    consisting of pyridine, pyrazine, and isoxazole.-   Preferably, A, B¹ and B² are CH; B¹ is N and B² and A are CH; or A    is absent, B¹ is CH, and B² is O.-   More preferably, the A- and B-containing ring is pyridine.-   More preferably, the A- and B-containing ring is a 3,6-disubstituted    pyridine.-   More preferably, the A- and B-containing ring is a 2,5-disubstituted    pyridine.-   More preferably, the A- and B-containing ring is a 2,5-disubstituted    pyrazine.-   More preferably, the A- and B-containing ring is a 3,5-disubstituted    isoxazole.-   Even more preferably, A is CH or A is absent.-   Even more preferably, B¹ is CH or N.-   Even more preferably, B² is CH or O.-   Preferably, L is methylene.-   Preferably, Q is selected from the group consisting of propylenoxy,    ethylenoxy, propyn-1-ylene, butyn-1-ylene, carbonyl, and    thiocarbonyl.-   Preferably, Q is propylenoxy, butyn-1-ylene, or carbonyl.-   Preferably, Q is carbonyl.-   Preferably, R¹ is independently selected from the group consisting    of —H, methyl, ethyl, propyl, isopropyl, butyl, isobutyl,    methoxyethyl, hydroxyethyl, piperidinylethyl, morpholinylethyl,    pyridylethyl, diethylaminoethyl, propenyl, propargyl, cyclopropyl,    cyclopentyl, cyclohexyl, phenyl, benzyl, pyridinyl, pyrrolyl,    pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, and    azepanyl.-   More preferably, R¹ is independently selected from the group    consisting of —H, methyl, ethyl, propyl, isopropyl, butyl, isobutyl,    methoxyethyl, cyclopropyl, piperidinylethyl, morpholinylethyl,    pyridylethyl, and diethylaminoethyl.-   Even more preferably, R¹ is independently selected from the group    consisting of —H, methyl, and methoxyethyl.-   Preferably, R² is independently selected from the group consisting    of methyl, ethyl, propyl, isopropyl, butyl, isobutyl, methoxyethyl,    hydroxyethyl, piperidinylethyl, morpholinylethyl, pyridylethyl,    diethylaminoethyl, propenyl, propargyl, cyclopropyl, cyclopentyl,    cyclohexyl, phenyl, benzyl, pyridinyl, pyrrolyl, pyrrolidinyl,    piperidinyl, morpholinyl, thiomorpholinyl, and azepanyl.-   More preferably, R² is independently selected from the group    consisting of methyl, ethyl, propyl, isopropyl, butyl, isobutyl,    methoxyethyl, cyclopropyl, piperidinylethyl, morpholinylethyl,    pyridylethyl, and diethylaminoethyl.-   Even more preferably, R² is independently selected from the group    consisting of methyl and methoxyethyl.-   Preferably, where R¹ and R² are taken together with the nitrogen of    attachment to form a ring, said ring is selected from the group    consisting of piperidine, morpholine, thiomorpholine, piperazine,    and pyrrolidine.-   More preferably, R¹ and R² may be taken together with the nitrogen    of attachment to form a ring selected from the group consisting of    piperidine, morpholine, and piperazine.-   In an alternative embodiment, R¹ and R² may be taken together with    the nitrogen of attachment to form 4-fluoropiperidine.-   Even more preferably, R¹ and R² may be taken together with the    nitrogen of attachment to form a ring selected from the group    consisting of piperidine and morpholine.-   Preferably, R³ is independently selected from the group consisting    of —H, methyl, ethyl, propyl, isopropyl, butyl, isobutyl,    methoxyethyl, hydroxyethyl, piperidinylethyl, morpholinylethyl,    pyridylethyl, diethylaminoethyl, propenyl, propargyl, cyclopropyl,    cyclopentyl, cyclohexyl, phenyl, benzyl, pyridinyl, pyrrolyl,    pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, and    azepanyl.-   More preferably, R³ is independently selected from the group    consisting of —H, methyl, ethyl, propyl, isopropyl, butyl, isobutyl,    methoxyethyl, cyclopropyl, piperidinylethyl, morpholinylethyl,    pyridylethyl, and diethylaminoethyl.-   Even more preferably, R³ is independently selected from the group    consisting of —H, methyl, and methoxyethyl.-   Preferably, R⁴ is independently selected from the group consisting    of methyl, ethyl, propyl, isopropyl, butyl, isobutyl, methoxyethyl,    hydroxyethyl, piperidinylethyl, morpholinylethyl, pyridylethyl,    diethylaminoethyl, propenyl, propargyl, cyclopropyl, cyclopentyl,    cyclohexyl, phenyl, benzyl, pyridinyl, pyrrolyl, pyrrolidinyl,    piperidinyl, morpholinyl, thiomorpholinyl, and azepanyl.-   More preferably, R⁴ is independently selected from the group    consisting of methyl, ethyl, propyl, isopropyl, butyl, isobutyl,    methoxyethyl, cyclopropyl, piperidinylethyl, morpholinylethyl,    pyridylethyl, and diethylaminoethyl.-   Even more preferably, R⁴ is independently selected from the group    consisting of methyl and methoxyethyl.-   Preferably, where R³ and R⁴ are taken together with the nitrogen of    attachment to form a ring, said ring is selected from the group    consisting of piperidine, morpholine, thiomorpholine, piperazine,    and pyrrolidine.-   More preferably, R³ and R⁴ may be taken together with the nitrogen    of attachment to form a ring selected from the group consisting of    piperidine, morpholine, and piperazine.-   In an alternative embodiment, R³ and R⁴ may be taken together with    the nitrogen of attachment to form 4-fluoropiperidine.-   Even more preferably, R³ and R⁴ may be taken together with the    nitrogen of attachment to form a ring selected from the group    consisting of piperidine and piperazine.

Any of the preferred substituents described above that can be optionallyfurther substituted with any of R^(p), R^(q), R^(s), or R^(t) accordingto formula (I) are intended to be so optionally substituted.

It is understood that some compounds referred to herein are chiraland/or have geometric isomeric centers, for example E- and Z-isomers.The present invention encompasses all such optical isomers, includingstereoisomers and racemic mixtures, diastereomers, and geometric isomersthat possess the activity that characterizes the compounds of thisinvention. Compounds of the invention may exist as single enantiomers,mixtures of enantiomers, or racemic mixtures. In certain embodiments,the absolute configuration of a single enantiomer may be unknown. Inaddition, certain compounds referred to herein can exist in solvated aswell as unsolvated forms. It is understood that this inventionencompasses all such solvated and unsolvated forms that possess theactivity that characterizes the compounds of this invention.

Compounds according to the present invention that have been modified tobe detectable by some analytic technique are also within the scope ofthis invention. The compounds of the present invention may be labeledwith radioactive elements such as ¹²⁵I, ¹⁸F, ¹¹C, ⁶⁴Cu, and the like foruse in imaging or for radioactive treatment of patients. An example ofsuch compounds is an isotopically labeled compound, such as an ¹⁸Fisotopically labeled compound that may be used as a probe in detectionand/or imaging techniques, such as positron emission tomography (PET)and single-photon emission computed tomography (SPECT). Preferably,compounds of the present invention labeled with ¹⁸F or ¹¹C may be usedas a positron emission tomography (PET) molecular probe for studyingdisorders mediated by the histamine H₃ receptor and the serotonintransporter. Another example of such compounds is an isotopicallylabeled compound, such as a deuterium and/or tritium labeled compoundthat may be used in reaction kinetic studies. The compounds describedherein may be reacted with an appropriate functionalized radioactivereagents using conventional chemistry to provide radiolabeled compounds.

Pharmaceutically acceptable salts, esters, and amides includecarboxylate salts (e.g., C₁₋₈alkyl, C₃₋₈cycloalkyl, aryl,C₂₋₁₀heteroaryl, or C₂₋₁₀ non-aromatic heterocyclic), amino additionsalts, acid addition salts, esters, and amides that are within areasonable benefit/risk ratio, pharmacologically effective and suitablefor contact with the tissues of patients without undue toxicity,irritation, or allergic response. Representative salts for compounds offormula (I) displaying basic functionality include hydrobromide,hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate, valerate,oleate, palmitate, stearate, laurate, borate, benzoate, lactate,phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate,naphthylate, mesylate, glucoheptonate, lactiobionate, andlaurylsulfonate. Representative addition salts for compounds of formula(I) displaying acidic functionality are those that form non-toxic basesalts with such compounds. These salts may include alkali metal andalkali earth cations such as sodium, potassium, calcium, and magnesium,as well as non-toxic ammonium, quaternary ammonium, and amine cationssuch as tetramethyl ammonium, methylammonium, trimethylammonium, andethylammonium. See example, S. M. Berge, et al., “Pharmaceutical Salts,”J. Pharm. Sci., 1977, 66:1-19, which is incorporated herein byreference.

The present invention includes within its scope prodrugs of thecompounds of this invention. In general, such prodrugs will befunctional derivatives of the compounds that are readily convertible invivo into the required compound. Thus, in the methods of treatment ofthe present invention, the term “administering” shall encompass thetreatment of the various disorders described with the compoundspecifically disclosed or with a compound that may not be specificallydisclosed, but which converts to the specified compound in vivo afteradministration to the patient. Conventional procedures for the selectionand preparation of suitable prodrug derivatives are described, forexample, in “Design of Prodrugs”, ed. H. Bundgaard, Elsevier, 1985. Inaddition to salts, the invention provides the esters, amides, and otherprotected or derivatized forms of the described compounds.

Representative pharmaceutically acceptable amides of the inventioninclude those derived from ammonia, primary C₁₋₆ alkyl amines andsecondary di(C₁₋₆alkyl)amines. Secondary amines include 5- or 6-memberedheterocyclic or heteroaromatic ring moieties containing at least onenitrogen atom and optionally between 1 and 2 additional heteroatoms.Preferred amides are derived from ammonia, C₁₋₃alkyl primary amines, anddi(C₁₋₂alkyl)amines. Representative pharmaceutically acceptable estersof the invention include C₁₋₇alkyl, C₅₋₇cycloalkyl, phenyl, andphenyl(C₁₋₆)alkyl esters. Preferred esters include methyl esters.

The present invention includes within its scope prodrugs of thecompounds of this invention. In general, such prodrugs will befunctional derivatives of the compounds that are readily convertible invivo into the required compound. Thus, in the methods of treatment ofthe present invention, the term “administering” shall encompass thetreatment of the various disorders described with the compoundspecifically disclosed or with a compound that may not be specificallydisclosed, but which converts to the specified compound in vivo afteradministration to the patient. Conventional procedures for the selectionand preparation of suitable prodrug derivatives are described, forexample, in “Design of Prodrugs”, ed. H. Bundgaard, Elsevier, 1985. Inaddition to salts, the invention provides the esters, amides, and otherprotected or derivatized forms of the described compounds.

Preferred compounds of the present invention are selected from the groupconsisting of:

EX Compound Name 1(4-Isopropyl-piperazin-1-yl)-(6-piperidin-1-ylmethyl-pyridin-3-yl)-methanone; 2(4-Isopropyl-piperazin-1-yl)-(6-morpholin-4-ylmethyl-pyridin-3-yl)-methanone; 3(4-Isopropyl-piperazin-1-yl)-(5-piperidin-1-ylmethyl-pyridin-2-yl)-methanone; 4 2-Piperdin-1-ylmethyl-5-(3-piperdin-1-yl-propoxy)-pyridine;5 4-[5-(3-Piperidin-1-yl-propoxy)-pyridin-2-ylmethyl]-morpholine; 65-Piperidin-1-ylmethyl-2-(3-piperidin-1-yl-propoxy)-pyridine; 74-[6-(3-Piperidin-1-yl-propoxy)-pyridin-3-ylmethyl]-morpholine; 82-(4-Piperidin-1-yl-but-1-ynyl)-5-piperidin-1-ylmethyl-pyridine; 9(4-Isopropyl-piperazin-1-yl)-[6-(2-piperidin-1-yl-ethylamino)-pyridin-3-yl]-methanone; 10(4-Isopropyl-piperazin-1-yl)-[6-(2-morpholin-4-yl-ethylamino)-pyridin-3-yl]-methanone; 11(4-Isopropyl-piperazin-1-yl)-[6-(2-pyridin-2-yl-ethylamino)-pyridin-3-yl]-methanone; 12{6-[(2-Diethylamino-ethyl)-methyl-amino]-pyridin-3-yl}-(4-isopropyl-piperazin-1-yl)-methanone; 13(4-Isopropyl-piperazin-1-yl)-[6-(4-isopropyl-piperazin-1-yl)-pyridin-3-yl]-methanone; 144-[5-(4-Isopropyl-piperazine-1-carbonyl)-pyridin-2-yl]-piperazine-1-carboxylic acid ethyl ester; 15(4-Isopropyl-piperazin-1-yl)-[6-(4-methyl-piperazin-1-yl)-pyridin-3-yl]-methanone; 16(4-Isopropyl-piperazin-1-yl)-[2-(2-piperidin-1-yl-ethylamino)-pyridin-4-yl]-methanone; 17(4-Isopropyl-piperazin-1-yl)-[2-(2-piperidin-1-yl-ethylamino)-pyridin-3-yl]-methanone; 183-(4-Piperidin-1-yl-but-1-ynyl)-5-piperidin-1-ylmethyl-pyridine; 194-[5-(4-Piperidin-1-yl-but-1-ynyl)-pyridin-3-ylmethyl]-morpholine; 202-(4-Piperidin-1-yl-but-1-ynyl)-6-piperidin-1-ylmethyl-pyridine; 214-[6-(4-Piperidin-1-yl-but-1-ynyl)-pyridin-2-ylmethyl]-morpholine; 22(2-Methoxy-ethyl)-[6-(4-piperidin-1-yl-but-1-ynyl)-pyridin-2-ylmethyl]-amine; 23(4-Isopropyl-piperazin-1-yl)-(5-piperidin-1-ylmethyl-pyrazin-2-yl)-methanone; 24(4-Isopropyl-piperazin-1-yl)-(5-morpholin-4-ylmethyl-pyrazin-2-yl)-methanone; 254-[3-(3-Piperidin-1-yl-propoxy)-isoxazol-5-ylmethyl]-piperidine; 264-[3-(3-Piperidin-1-yl-propoxy)-isoxazol-5-ylmethyl]-morpholine; 27(2-Methoxy-ethyl)-[3-(3-piperidin-1-yl-propoxy)-isoxazol-5-ylmethyl]-amine; and 28(4-Isopropyl-piperazin-1-yl)-(6-piperidin-1-ylmethyl-pyridin-3-yl)-methanethione.

In a preferred embodiment, compounds of the present invention areselected from the group consisting of:

EX Compound Name 1(4-Isopropyl-piperazin-1-yl)-(6-piperidin-1-ylmethyl-pyridin-3-yl)-methanone; 2(4-Isopropyl-piperazin-1-yl)-(6-morpholin-4-ylmethyl-pyridin-3-yl)-methanone; 3(4-Isopropyl-piperazin-1-yl)-(5-piperidin-1-ylmethyl-pyridin-2-yl)-methanone; 4 2-Piperdin-1-ylmethyl-5-(3-piperdin-1-yl-propoxy)-pyridine;5 4-[5-(3-Piperidin-1-yl-propoxy)-pyridin-2-ylmethyl]-morpholine; 82-(4-Piperidin-1-yl-but-1-ynyl)-5-piperidin-1-ylmethyl-pyridine; 9(4-Isopropyl-piperazin-1-yl)-[6-(2-piperidin-1-yl-ethylamino)-pyridin-3-yl]-methanone; 10(4-Isopropyl-piperazin-1-yl)-[6-(2-morpholin-4-yl-ethylamino)-pyridin-3-yl]-methanone; 12{6-[(2-Diethylamino-ethyl)-methyl-amino]-pyridin-3-yl}-(4-isopropyl-piperazin-1-yl)-methanone; 13(4-Isopropyl-piperazin-1-yl)-[6-(4-isopropyl-piperazin-1-yl)-pyridin-3-yl]-methanone; 15(4-Isopropyl-piperazin-1-yl)-[6-(4-methyl-piperazin-1-yl)-pyridin-3-yl]-methanone; 16(4-Isopropyl-piperazin-1-yl)-[2-(2-piperidin-1-yl-ethylamino)-pyridin-4-yl]-methanone; 183-(4-Piperidin-1-yl-but-1-ynyl)-5-piperidin-1-ylmethyl-pyridine; 194-[5-(4-Piperidin-1-yl-but-1-ynyl)-pyridin-3-ylmethyl]-morpholine; 202-(4-Piperidin-1-yl-but-1-ynyl)-6-piperidin-1-ylmethyl-pyridine; 214-[6-(4-Piperidin-1-yl-but-1-ynyl)-pyridin-2-ylmethyl]-morpholine; 22(2-Methoxy-ethyl)-[6-(4-piperidin-1-yl-but-1-ynyl)-pyridin-2-ylmethyl]-amine; 23(4-Isopropyl-piperazin-1-yl)-(5-piperidin-1-ylmethyl-pyrazin-2-yl)-methanone; 24(4-Isopropyl-piperazin-1-yl)-(5-morpholin-4-ylmethyl-pyrazin-2-yl)-methanone; 254-[3-(3-Piperidin-1-yl-propoxy)-isoxazol-5-ylmethyl]-piperidine; and 28(4-Isopropyl-piperazin-1-yl)-(6-piperidin-1-ylmethyl-pyridin-3-yl)-methanethione.

In another preferred embodiment, compounds of the present invention areselected from the group consisting of:

EX Compound Name 1(4-Isopropyl-piperazin-1-yl)-(6-piperidin-1-ylmethyl-pyridin-3-yl)-methanone; 3(4-Isopropyl-piperazin-1-yl)-(5-piperidin-1-ylmethyl-pyridin-2-yl)-methanone; 4 2-Piperdin-1-ylmethyl-5-(3-piperdin-1-yl-propoxy)-pyridine;8 2-(4-Piperidin-1-yl-but-1-ynyl)-5-piperidin-1-ylmethyl-pyridine; 9(4-Isopropyl-piperazin-1-yl)-[6-(2-piperidin-1-yl-ethylamino)-pyridin-3-yl]-methanone; 12{6-[(2-Diethylamino-ethyl)-methyl-amino]-pyridin-3-yl}-(4-isopropyl-piperazin-1-yl)-methanone; 13(4-Isopropyl-piperazin-1-yl)-[6-(4-isopropyl-piperazin-1-yl)-pyridin-3-yl]-methanone; 15(4-Isopropyl-piperazin-1-yl)-[6-(4-methyl-piperazin-1-yl)-pyridin-3-yl]-methanone; 16(4-Isopropyl-piperazin-1-yl)-[2-(2-piperidin-1-yl-ethylamino)-pyridin-4-yl]-methanone; 183-(4-Piperidin-1-yl-but-1-ynyl)-5-piperidin-1-ylmethyl-pyridine; 202-(4-Piperidin-1-yl-but-1-ynyl)-6-piperidin-1-ylmethyl-pyridine; 23(4-Isopropyl-piperazin-1-yl)-(5-piperidin-1-ylmethyl-pyrazin-2-yl)-methanone; 254-[3-(3-Piperidin-1-yl-propoxy)-isoxazol-5-ylmethyl]-piperidine; and 28(4-Isopropyl-piperazin-1-yl)-(6-piperidin-1-ylmethyl-pyridin-3-yl)-methanethione.

The features and advantages of the invention are apparent to one ofordinary skill in the art. Based on this disclosure, including thesummary, detailed description, background, examples, and claims, one ofordinary skill in the art will be able to make modifications andadaptations to various conditions and usages. Publications describedherein are incorporated by reference in their entirety. Where chemicalsymbols are used, it is understood that they are read from left toright, and that otherwise their spatial orientation has no significance.

The compounds as described above may be made according to processeswithin the skill of the art and/or that are described in the schemes andexamples that follow. To obtain the various compounds herein, startingmaterials may be employed that carry the ultimately desired substituentsthough the reaction scheme with or without protection as appropriate.This may be achieved by means of conventional protecting groups, such asthose described in “Protective Groups in Organic Chemistry”, ed. J. F.W. McOmie, Plenum Press, 1973; and T. W. Greene & P. G. M. Wuts,“Protective Groups in Organic Synthesis”, 3^(rd) ed., John Wiley & Sons,1999. The protecting groups may be removed at a convenient subsequentstage using methods known from the art. Alternatively, it may benecessary to employ, in the place of the ultimately desired substituent,a suitable group that may be carried through the reaction scheme andreplaced as appropriate with the desired substituent. Such compounds,precursors, or prodrugs are also within the scope of the invention.

The compounds as described above may be made according to Schemes A-Gbelow. Persons skilled in the art will recognize that certain compoundsare more advantageously produced by one scheme as compared to the other.

Compounds of formula (I) may be prepared as shown in Scheme A, with thefollowing notes and additions. Commercially available heterocyclic esterderivatives (II) may be oxidized to the corresponding aldehydes (III) ata benzylic methyl position under conditions such as I₂, t-butylchloride, TFA, and DMSO. This transformation may also be accomplished intwo steps by debromination of the methyl substituent usingN-bromosuccinimide and dibenzoyl peroxide, followed by reaction of thedibromide with silver nitrate in ethanol with heating to form thealdehyde. The aldehyde functionality can then be reacted underconditions of reductive amination to provide compounds of formula (IV).The aldehyde can be treated with a suitable amine, with or without theaddition of an activating agent such as a protic or Lewis acid, and withan appropriate reducing agent such as sodium triacetoxyborohydride. Thealdehyde may alternatively be reduced to an alcohol, converted to aleaving group such as a chloride and displaced with an appropriate amineas shown below in Scheme G. The chloride could also be displaced withcyanide anion, and the resulting nitrile reduced to homologate thelinker by one additional carbon. Alternatively, the aldehyde may bereacted using Horner-Emmons chemistry followed by hydrogenation of thedouble bond to introduce an alkyl chain containing an additional twocarbons. The ester can be converted to a range of amides of formula (I)using a primary or secondary amine, in the presence of a Lewis acidactivating agent such as MgBr₂. The carboxamide may be converted to itscorresponding thioamides of formula (I) by treatment with P₂S₅ orLawesson's reagent.

Compounds of formula (I) may also be prepared as shown in Scheme B, withthe following notes and additions. Acid derivatives (V) can be convertedto their corresponding amides (VI) under standard peptide couplingconditions, with an appropriate primary or secondary amine, in thepresence of coupling agents such as 1-hydroxybenzotriazole hydrate(HOBt), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide HCl (EDCI), andN-methylmorpholine. Selective reduction of the ester group to thealdehyde (VII) may be performed with DIBAL-H, or a two-step sequence canbe employed wherein the ester is reduced to the alcohol with a hydrideagent such as LiAlH(otBu)₃ or NaBH₄, followed by oxidation to thealdehyde with MnO₂, Dess-Martin periodinane, or Swern oxidation. Thealdehyde would be converted into compounds of formula (I) where Q iscarbonyl or thiocarbonyl, using the methods described for Scheme A.

Alternatively, compounds of formula (I) may also be produced as shown inScheme C, with the following notes and additions. Heterocyclic hydroxyacids (VIII) may be reacted under peptide coupling conditions with aprimary or secondary amine as described above to form amides (IX). Theamide functionality may be reduced to the corresponding amine (X) usingan appropriate reducing agent such as borane-dimethylsulfide. Thehydroxyl functionality may be alkylated with a suitable alkylating agentto install the hydrocarbon linker (XI), such as 1-bromo-3-chloropropaneor 1-bromo-4-chloropropane, in the presence of a suitable base such asK₂CO₃. To achieve the desired O-regioselectivity of the alkylation,Ag₂CO₃ may be used. The tethered leaving group may be displaced with aprimary or secondary amine, with or without the addition of catalyticKI, and in the presence of a suitable base such as Na₂CO₃.Alternatively, compounds of formula (X) may be converted directly tocompounds of formula (I) under Mitsunobu conditions with anamine-functionalized alcohol such as 3-piperidin-1-ylpropanol, standardor polymer-supported triphenylphosphine, and di-t-butylazodicarboxylate, in a solvent such as dichloromethane.

Compounds of formula (I) may also be prepared as described in Scheme D,with the following notes and additions. Compounds of formula (XII) whereX is bromide may be converted to bromo aldehydes (XIII) by treatmentwith an organolithium reagent such as n-BuLi, and quenching the lithiumanion with DMF. The intermediate lithium species may be converted tocorresponding Grignard reagent in situ via treatment with n-BuMgCl.Bromo aldehydes can be prepared from commercially available carboxylicacids using methods known to one skilled in the art. The aldehydes(XIII) can be transformed into amines (XIV) using reductive aminationconditions as described above. Alternatively, alcohols of formula (X)may be converted to the corresponding triflates (XIV, X═OTf) usingreagents such as N-phenyltrifluoromethane-sulfonimide or triflicanhydride, in the presence of a tertiary amine base such astriethylamine. The triflates and bromides may be coupled, typicallyunder conditions of palladium catalysis, with terminal alkynes suitablyfunctionalized with an amine substituent, such as1-but-3-ynyl-piperidine (Turner, S. C. et al. Bioorg. Med. Chem. Lett.2003, 13(13):2131-2136) in the presence of a palladium catalyst such as(PPh₃)₂PdCl₂, with or without additives such as CuI, triphenylphosphine,and triethylamine, to form compounds of formula (I).

Compounds of formula (I) may also be prepared as shown in Scheme E, withthe following notes and additions. 2-Bromo substituted heterocycles offormula (XIV), prepared as described in Scheme D, may be converted tocompounds of formula (I) by displacement with a suitable alkoxidereagent, formed by reaction of the desired subunit such as3-piperidin-1-yl-propan-1-ol and the bromide in the presence of a strongbase such as sodium hydride.

Compounds of formula (I) may also be prepared as shown in Scheme F, withthe following notes and additions. Heterocyclic acids (XV) with a2-chloro substituent may be converted to the corresponding amides (XVI)as described above. The chloride may be displaced by an appropriateprimary or secondary amine, with or without heating, in a solvent suchas n-BuOH, to form compounds of formula (I) where L is absent.

Referring to Scheme G, there are the following notes and additions. Thefree hydroxyl group in isoxazoles (XVII) may be alkylated underMitsunobu conditions, using a suitably functionalized amino alcohol suchas 3-piperidin-1-yl-propan-1-ol, polymer-supported triphenylphosphine,and di-t-butyl azodicarboxylate, in a solvent such as dichloromethane.The alcohol could also be converted to amine (XVIII) using alkylationand displacement steps described above. The ester functionality may bereduced to form alcohols of formula (XIX). The alcohol may be convertedto the corresponding chloride with thionyl chloride, and subsequentlydisplaced with a suitable primary or secondary amine to form compoundsof formula (I). Alternatively, the alcohol may be oxidized to thecorresponding aldehyde and transformed under conditions of reductiveamination as described above.

Compounds prepared according to the schemes described above may beobtained as single enantiomers, mixtures of enantiomers, or racemicmixtures. Where racemic (1:1) and non-racemic (not 1:1) mixtures ofenantiomers are obtained, single enantiomers may be isolated usingconventional separation methods known to one skilled in the art.Particularly useful separation methods may include chiralchromatography, recrystallization, resolution, diastereomeric saltformation, or derivatization into diastereomeric adducts followed byseparation.

The compounds of the present invention are modulators of the histamineH₃ receptor, and as such, the compounds are useful in the treatment ofhistamine H₃-mediated disease states.

Compounds of the present invention may be administered in pharmaceuticalcompositions to treat patients (humans and other mammals) with disordersmediated by the H₃ receptor. The disclosed compounds, alone or incombination (with, for example, a histamine H₁ receptor antagonist), areuseful for treating or preventing neurologic disorders includingsleep/wake and arousal/vigilance disorders (e.g. insomnia and jet lag),attention deficit hyperactivity disorders (ADHD), learning and memorydisorders, cognitive dysfunction, migraine, neurogenic inflammation,dementia, mild cognitive impairment (pre-dementia), Alzheimer's disease,epilepsy, narcolepsy with or without associated cataplexy, cataplexy,disorders of sleep/wake homeostasis, idiopathic somnolence, excessivedaytime sleepiness (EDS), circadian rhythm disorders, sleep/fatiguedisorders, fatigue, drowsiness associated with sleep apnea, sleepimpairment due to perimenopausal hormonal shifts, Parkinson's-relatedfatigue, MS-related fatigue, depression-related fatigue,chemotherapy-induced fatigue, eating disorders, obesity, motionsickness, vertigo, schizophrenia, substance abuse, bipolar disorders,manic disorders and depression, as well as other histamine H₃ receptormediated disorders such as upper airway allergic response, asthma, itch,nasal congestion and allergic rhinitis in a subject in need thereof.Excessive daytime sleepiness (EDS) may occur with or without associatedsleep apnea, shift work, fibromyalgia, MS, and the like.

The present invention also provides pharmaceutical compositionscomprising one or more compounds of this invention in association with apharmaceutically acceptable carrier and optionally additionalpharmaceutical agents such as H₁ antagonists, SSRIs, or modafinil. Thepharmaceutical compositions can be prepared using conventionalpharmaceutical excipients and compounding techniques known to thoseskilled in the art of preparing dosage forms. It is anticipated that thecompounds of the invention can be administered by oral, parenteral,rectal, topical, or ocular routes, or by inhalation. Preparations mayalso be designed to give slow release of the active ingredient. Thepreparation may be in the form of tablets, capsules, sachets, vials,powders, granules, lozenges, powders for reconstitution, liquidpreparations, or suppositories. Preferably, compounds may beadministered by intravenous infusion or topical administration, but morepreferably by oral administration.

For oral administration, the compounds of the invention can be providedin the form of tablets or capsules, or as a solution, emulsion, orsuspension. Tablets for oral use may include the active ingredient mixedwith pharmaceutically acceptable excipients such as inert diluents,disintegrating agents, binding agents, lubricating agents, sweeteningagents, flavoring agents, coloring agents and preservatives agents.Suitable inert fillers include sodium and calcium carbonate, sodium andcalcium phosphate, lactose, starch, sugar, glucose, methyl cellulose,magnesium stearate, mannitol, sorbitol, and the like; typical liquidoral excipients include ethanol, glycerol, water and the like. Starch,polyvinyl-pyrrolidone, sodium starch glycolate, microcrystallinecellulose, and alginic acid are suitable disintegrating agents. Bindingagents may include starch and gelatin. The lubricating agent, ifpresent, will generally be magnesium stearate, stearic acid or talc. Ifdesired, the tablets may be coated with a material such as glycerylmonostearate or glyceryl distearate to delay absorption in thegastrointestinal tract, or may be coated with an enteric coating.Capsules for oral use include hard gelatin capsules in which the activeingredient is mixed with a solid, semi-solid, or liquid diluent, andsoft gelatin capsules wherein the active ingredient is mixed with water,an oil such as peanut oil or olive oil, liquid paraffin, a mixture ofmono and di-glycerides of short chain fatty acids, polyethylene glycol400, or propylene glycol.

Liquids for oral administration may be suspensions, solutions, emulsionsor syrups or may be presented as a dry product for reconstitution withwater or other suitable vehicles before use. Compositions of such liquidmay contain pharmaceutically-acceptable excipients such as suspendingagents (for example, sorbitol, methyl cellulose, sodium alginate,gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminiumstearate gel and the like); non-aqueous vehicles, which include oils(for example, almond oil or fractionated coconut oil), propylene glycol,ethyl alcohol or water; preservatives (for example, methyl or propylp-hydroxybenzoate or sorbic acid); wetting agents such as lecithin; and,if needed, flavoring or coloring agents.

The compounds of this invention may also be administered by non-oralroutes. The compositions may be formulated for rectal administration asa suppository. For parenteral use, including intravenous, intramuscular,intraperitoneal, or subcutaneous routes, the compounds of the inventionwill generally be provided in sterile aqueous solutions or suspensions,buffered to an appropriate pH and isotonicity or in parenterallyacceptable oil. Suitable aqueous vehicles include Ringer's solution andisotonic sodium chloride. Such forms will be presented in unit dose formsuch as ampules or disposable injection devices, in multi-dose formssuch as vials from which the appropriate dose may be withdrawn, or in asolid form or pre-concentrate that can be used to prepare an injectableformulation. Another mode of administration of the compounds of theinvention may utilize a patch formulation to affect transdermaldelivery. The compounds of this invention may also be administered byinhalation, via the nasal or oral routes using a spray formulationconsisting of the compound of the invention and a suitable carrier.

Effective doses of the compounds of the present invention may beascertained by conventional methods. The specific dosage level requiredfor any particular patient will depend on a number of factors, includingseverity of the condition being treated, the route of administration,and the weight of the patient. In general, however, it is anticipatedthat the daily dose (whether administered as a single dose or as divideddoses) will be in the range 0.01 to 1000 mg per day, more usually from 1to 500 mg per day, and most usually from 10 to 200 mg per day. Expressedas dosage per unit body weight, a typical dose will be expected to bebetween 0.0001 mg/kg and 15 mg/kg, especially between 0.01 mg/kg and 7mg/kg, and most especially between 0.15 mg/kg and 2.5 mg/kg.

Preferably, oral doses range from about 0.05 to 200 mg/kg, daily, takenin 1 to 4 separate doses. Some compounds of the invention may be orallydosed in the range of about 0.05 to about 50 mg/kg daily, others may bedosed at 0.05 to about 20 mg/kg daily, while still others may be dosedat 0.1 to about 10 mg/kg daily. Infusion doses can range from about 1 to1000 μg/kg/min of inhibitor, admixed with a pharmaceutical carrier overa period ranging from several minutes to several days. For topicaladministration compounds of the present invention may be mixed with apharmaceutical carrier at a concentration of about 0.1% to about 10% ofdrug to vehicle.

The disclosed compounds are useful in combination with other therapeuticagents, including H₁ receptor antagonists, H₂ receptor antagonists, andneurotransmitter modulators such as SSRIs, serotonin-norepinephrinereuptake inhibitors, noradrenergic reuptake inhibitors, non-selectiveserotonin re-uptake inhibitors (NSSRIs), or other neuroactive agentssuch as modafinil.

Methods are known in the art for determining effective doses fortherapeutic and prophylactic purposes for the disclosed pharmaceuticalcompositions or the disclosed drug combinations, whether or notformulated in the same composition. For therapeutic purposes, the term“jointly effective amount” as used herein, means that amount of eachactive compound or pharmaceutical agent, alone or in combination, thatelicits the biological or medicinal response in a tissue system, animalor human that is being sought by a researcher, veterinarian, medicaldoctor or other clinician, which includes alleviation of the symptoms ofthe disease or disorder being treated. For prophylactic purposes (i.e.,inhibiting the onset or progression of a disorder), the term “jointlyeffective amount” refers to that amount of each active compound orpharmaceutical agent, alone or in combination, that inhibits in asubject the onset or progression of a disorder as being sought by aresearcher, veterinarian, medical doctor or other clinician, thedelaying of which disorder is mediated, at least in part, by themodulation of one or more histamine receptors. Thus, the presentinvention provides combinations of two or more drugs wherein, forexample, (a) each drug is administered in an independentlytherapeutically or prophylactically effective amount; (b) at least onedrug in the combination is administered in an amount that issub-therapeutic or sub-prophylactic if administered alone, but istherapeutic or prophylactic when administered in combination with thesecond or additional drugs according to the invention; or (c) both drugsare administered in an amount that is sub-therapeutic orsub-prophylactic if administered alone, but are therapeutic orprophylactic when administered together. Combinations of three or moredrugs are analogously possible. Methods of combination therapy includeco-administration of a single formulation containing all active agents;essentially contemporaneous administration of more than one formulation;and administration of two or more active agents separately formulated.

EXAMPLES

In order to illustrate the invention, the following examples areincluded. These examples do not limit the invention. They are only meantto suggest a method of practicing the invention. Those skilled in theart may find other methods of practicing the invention, which areobvious to them. However, those methods are deemed to be within thescope of this invention.

Protocol for Preparative Reversed-Phase HPLC Gilson ® instrument Column:YMC-Pack ODS-A, 5 μm, 75 × 30 mm Flow rate: 10 mL/min Detection: λ = 220& 254 nm Gradient (acetonitrile/H₂O, 0.05% trifluoroacetic acid) 1)  0.0min 20% acetonitrile/80% H₂O 2) 20.0 min 99% acetonitrile/1% H₂O

Protocol for HPLC (Reversed-Phase) Hewlett Packard Series 1100 Column:Agilent ZORBAX ® C8, 5 μm, 4.6 × 150 mm Flow rate: 1 mL/min Detection: λ= 220 & 254 nm Gradient (acetonitrile/H₂O, 0.05% trifluoroaceticacid) 1) 0.0 min  1% acetonitrile/99% H₂O 2) 8.0 min 99% acetonitrile/1%H₂O

Mass spectra were obtained on an Agilent series 1100 MSD usingelectrospray ionization (ESI) in either positive or negative modes asindicated.

NMR spectra were obtained on either a Bruker model DPX400 (400 MHz) orDPX500 (500 MHz) spectrometer. The format of the ¹H NMR data below is:chemical shift in ppm down field of the tetramethylsilane reference(multiplicity, coupling constant J in Hz, integration).

Example 1

(4-Isopropyl-piperazin-1-yl)-(6-piperidin-1-ylmethyl-pyridin-3-yl)-methanone

Step A. 6-Formyl-nicotinic acid methyl ester. A solution of 6-methylnicotinic acid methyl ester (1.00 g, 6.62 mmol), iodine (1.68 g, 6.62mmol), 2-iodo-2-methylpropane (0.478 g, 2.60 mmol) and trifluoroaceticacid (2.26 g, 19.8 mmol) in anhydrous DMSO was heated for 3 h at 160° C.The reaction mixture was cooled to room temperature (rt) and treatedwith 1 N aq. Na₂S₂O₃ (50 mL). The reaction mixture was adjusted to pH 10with 1 N aq. NaHCO₃. The reaction mixture was extracted with ethylacetate (3×100 mL). The combined organic phases were dried overanhydrous Na₂SO₄, filtered, and concentrated. Chromatography of theresidue (SiO₂; 0-3% EtOH:DCM) gave the title compound as a solid (0.506g, 46%).

Step B. 6-Piperidin-1-ylmethyl-nicotinic acid methyl ester. To asolution of 6-formyl-nicotinic acid methyl ester (0.200 g, 1.21 mmol)and piperidine (0.14 mL, 1.33 mmol) in DCM (15 mL) was added NaB(OAc)₃H(0.380 g, 1.80 mmol). After 18 h, the reaction was diluted with 1 N NaOH(10 mL) and extracted with DCM (2×50 mL). The organic layers werecombined, dried (Na₂SO₄), and concentrated. Chromatography of theresidue (SiO₂; 1-3% 2 M NH₃ in MeOH/DCM) gave the title compound as anoil (0.210 g, 74%).

Step C.(4-Isopropyl-piperazin-1-yl)-(6-piperidin-1-ylmethyl-pyridin-3-yl)-methanone.A solution of 6-piperidin-1-ylmethyl-nicotinic acid methyl ester (0.300g, 1.28 mmol), and MgBr₂·OEt₂ (0.900 g, 3.84 mmol) in THF (15 mL) wasstirred for 15 min. A solution of 1-isopropyl-piperazine (0.325 g, 2.56mmol) in THF (2 mL) was then added to the reaction drop-wise and themixture was heated at reflux for 48 h. The reaction mixture was cooledto rt, concentrated, treated with 1 N aq. NaHCO₃ (50 mL), and extractedwith ethyl acetate (3×50 mL). The organic layers were combined, dried(Na₂SO₄), and concentrated. Chromatography of the residue (SiO₂; 3-6% 2M NH₃ in MeOH/DCM) gave the title compound as an oil (0.297 g, 70%). MS(ESI): exact mass calcd. for C₁₉H₃₀N₄O, 330.2; m/z found, 331.2 [M+H]⁺.¹H NMR (400 MHz, CDCl₃): 8.55 (d, J=2.2, 1H), 7.87 (dd, J=7.8, 2.0, 1H),7.62 (d, J=7.6, 1H), 3.78 (br s, 2H), 3.67 (s, 2H), 3.48 (br s, 2H),2.77-2.73 (m, 1H), 2.65-2.48 (m, 8H), 1.65-1.59 (m, 4H), 1.49-1.48 (m,2H), 1.09 (d, J=6.6, 6H).

Example 2

(4-Isopropyl-piperazin-1-yl)-(6-morpholin-4-ylmethyl-pyridin-3-yl)-methanone

The title compound was synthesized in a similar manner as Example 1substituting morpholine for piperidine in step B. MS (ESI): exact masscalcd. for C₁₈H₂₈N₄O₂, 332.2; m/z found, 333.2 [M+H]⁺. ¹H NMR (400 MHz,CDCl₃): 8.60 (d, J=2.3, 1H), 7.72 (dd, J=7.8, 2.3, 1H), 7.48 (d, J=7.8,1H), 3.79-3.72 (m, 6H), 3.67 (s, 2H), 3.44 (br s, 2H), 2.75-2.72 (m,1H), 2.60 (br s, 2H), 2.52-2.48 (m, 6H), 1.05 (d, J=6.6, 6H).

Example 3

(4-Isopropyl-piperazin-1-yl)-(5-piperidin-1-ylmethyl-pyridin-2-yl)-methanone

Step A. 6-(4-Isopropyl-piperazine-1-carbonyl)-nicotinic acid methylester. To a solution of pyridine-2,5-dicarboxylic acid 5-methyl ester(1.00 g, 5.50 mmol) and 1-isopropyl-piperazine dihydrochloride (1.20 g,6.10 mmol) in DCM (100 mL) was added 1-hydroxybenzotriazole hydrate(HOBt, 1.10 g, 8.30 mmol),1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (EDC, 1.60g, 8.30 mmol), and N-methyl morpholine (2.9 mL, 27.0 mmol). After 18 h,the reaction mixture was quenched with 1 N aq. NaHCO₃ (50 mL) andextracted with DCM (3×50 mL). The organic layers were combined, dried(Na₂SO₄), and concentrated. Chromatography of the residue (SiO₂; 2-5% 2M NH₃ in MeOH/DCM) gave the title compound (1.20 g, 74%).

B.(5-Hydroxymethyl-pyridin-2-yl)-(4-isopropyl-piperazin-1-yl)-methanone. Asolution of 6-(4-isopropyl-piperazine-1-carbonyl)-nicotinic acid methylester (0.500 g, 1.72 mmol) in THF (15 mL) was cooled to −78° C. in a dryice bath. A solution of lithium tri-tert-butoxyaluminohydride (1 M inTHF, 3.44 mL) was then added drop-wise to the reaction mixture. Theresulting solution was allowed to come to rt and was stirred for 18 h.The reaction was quenched with satd. aq. potassium sodium tartrate(Rochelle's salt, 15 mL) and extracted with DCM (3×50 mL). The organiclayers were combined, dried (Na₂SO₄), and concentrated to give the titlecompound (0.275 g, 61%).

Step C. 6-(4-Isopropyl-piperazine-1-carbonyl)-pyridine-3-carbaldehyde.To a solution of(5-hydroxymethyl-pyridin-2-yl)-(4-isopropyl-piperazin-1-yl)-methanone(0.275 g, 1.10 mmol) in DCM (30 mL) was added MnO₂ (0.400 g., 5.20mmol). The reaction was stirred for 6 h, filtered through a pad ofdiatomaceous earth, and concentrated to give the desired aldehyde (0.250g, 95%).

Step D.(4-Isopropyl-piperazin-1-yl)-(5-piperidin-1-ylmethyl-pyridin-2-yl)-methanone.To a solution of6-(4-isopropyl-piperazine-1-carbonyl)-pyridine-3-carbaldehyde (0.250 g,0.96 mmol) and piperidine (0.11 mL, 1.10 mmol) in DCM (20 mL) was addedNaB(OAc)₃H (0.300 g, 1.44 mmol). After 18 h, 1 N NaOH (15 mL) was addedand the mixture was extracted with DCM (3×25 mL). The organic layerswere combined, dried (Na₂SO₄), and concentrated. Chromatography of theresulting residue (SiO₂: 4-8% 2 M NH₃ in MeOH/DCM) gave the titlecompound as an oil (0.030 g, 9%). MS (ESI): exact mass calcd. forC₁₉H₃₀N₄O, 330.2; m/z found, 331.5 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃): 8.49(s, 1H), 7.77 (dd, J=7.8, 2.0, 1H), 7.58 (d, J=7.8, 1H), 3.82 (t, J=5.0,2H), 3.61 (t, J=5.0, 2H), 3.49 (s, 2H), 2.75-2.72 (m, 1H), 2.62 (t,J=5.0, 2H), 2.51 (t, J=5.0, 2H), 2.37 (br s, 4H), 1.60-1.54 (m, 4H),1.45-1.43 (m, 2H), 1.05 (d, J=6.6, 6H).

Example 4

2-Piperidin-1-ylmethyl-5-(3-piperidin-1-yl-propoxy)-pyridine

Step A. (5-Hydroxy-pyridin-2-yl)-piperidin-1-yl-methanone. To a solutionof 5-hydroxy-2-pyridine carboxylic acid (2.00 g, 14.0 mmol) andpiperidine (1.5 mL, 15 mmol) in DCM (150 mL) was added HOBt (2.80 g,21.0 mmol), EDC (4.00 g, 21.0 mmol), and N-methyl morpholine (8.5 mL, 84mmol). After 18 h the reaction mixture was concentrated. Chromatographyof the residue (SiO₂; 5-10% 2 M NH₃ in MeOH/DCM) gave the title compoundas a solid (1.30 g, 43%).

Step B. 6-Piperidin-1-ylmethyl-Pyridin-3-ol. To a solution of(5-hydroxy-pyridin-2-yl)-piperidin-1-yl-methanone (1.30 g, 6.31 mmol) inTHF (100 mL) was added borane-dimethylsulfide complex (1.75 mL, 18.9mmol). After 18 h the solvent was removed and the residue was dilutedwith MeOH (50 mL) and heated to 60° C. After 2 h the solvent wasevaporated and chromatography of the residue (SiO₂: 4-8% 2 M NH₃ inMeOH/DCM) gave the title compound as an oil (0.225 g, 17%).

Step C. 5-(3-Chloro-propoxy)-2-Piperidin-1ylmethyl-pyridine. A solutionof 6-piperidin-1-ylmethyl-pyridin-3-ol (0.225 g, 1.17 mmol),1-bromo-3-chloro propane (0.23 mL, 2.34 mmol), and K₂CO₃ (0.483 g, 3.50mmol) in acetone (10 mL) was heated to reflux temperature. After 10 hthe reaction mixture was cooled to rt, diluted with acetone (50 mL) andfiltered through a pad of diatomaceous earth. The filtrate wasconcentrated, giving the crude title compound as an oil (0.250 g, 80%).

Step D. 2-Piperidin-1-ylmethyl-5-(3-piperidin-1-yl-propoxy)-pyridine. Asolution of 5-(3-chloro-propoxy)-2-piperidin-1-ylmethyl-pyridine (0.25g, 0.86 mmol), piperidine (0.09 mL, 0.94 mmol), KI (0.003 g, 0.017mmol), and Na₂CO₃ (0.045 g, 0.43 mmol) in 1-butanol (5 mL) was heated to95° C. After 18 h the reaction mixture was concentrated, diluted withDCM (50 mL) and filtered through a pad of diatomaceous earth. Thefiltrate was concentrated and chromatography of the residue (SiO₂: 3-8%2 M NH₃ in MeOH/DCM) gave the title compound as an oil (0.025 g, 10%).MS (ESI): exact mass calcd. for C₁₉H₃₁N₃O, 317.3; m/z found, 318.5. ¹HNMR (400 MHz, CDCl₃): 8.23 (d, J=2.8, 1H), 7.29 (d, J=8.1, 1H), 7.16(dd, J=8.6, 3.0, 1H), 4.03 (t, J=6.3, 2H), 3.55 (s, 2H), 2.48-2.40 (m,10H), 2.01-1.96 (m, 2H), 1.61-1.46 (m, 8H), 1.43 (br s, 4H).

Example 5

4-[5-(3-Piperidin-1-yl-propoxy)-pyridin-2-ylmethyl]-morpholine

This compound was prepared in a similar fashion as Example 4substituting morpholine for piperidine in step A. MS (ESI): exact masscalcd. for C₁₈H₂₉N₃O₂, 319.2; m/z found, 320.5 [M+H]⁺. ¹H NMR (400 MHz,CDCl₃): 8.24 (d, J=2.5, 1H), 7.28 (d, J=8.6, 1H), 7.16 (dd, J=8.3, 2.8,1H), 4.04 (t, J=6.3, 2H), 3.72 (t, J=4.7, 4H), 3.58 (s, 2H), 2.49-2.46(m, 6H), 2.39 (br s, 4H), 2.01-1.96 (m, 2H), 1.61-1.55 (m, 4H),1.45-1.43 (br s, 2H).

Example 6

5-Piperidin-1-ylmethyl-2-(3-piperidin-1-yl-propoxy)-pyridine

Step A. (6-Bromo-pyridin-3-yl)-piperidin-1-yl-methanone. Theintermediate is prepared in a similar fashion as described in Example 4,Step A, substituting 6-bromo-3-pyridine carboxylic acid for5-hydroxy-2-pyridine carboxylic acid.

Step B. 2-Bromo-5-piperidin-1-ylmethyl-pyridine. The intermediate isprepared in a similar fashion as described in Example 4, Step B,substituting (6-bromo-pyridin-3-yl)-piperidin-1-yl-methanone for(5-hydroxy-pyridin-2-yl)-piperidin-1-yl-methanone.

Step C. 5-Piperidin-1-ylmethyl-2-(3-piperidin-1-yl-propoxy)-pyridine. Toa suspension of NaH (1.5 mmol) in DMF is added3-piperidin-1-yl-propan-1-ol (1.1 mmol). After 30 min,2-bromo-5-piperidin-1-ylmethyl-pyridine (1 mmol) is added to themixture. After 18 h, the reaction is extracted with ethyl acetate (100mL) and washed with 1 N NaHCO₃ (50 mL) and H₂O (3×50 mL). The organiclayer is dried, concentrated, and chromatographed on SiO₂ to provide thetitle compound.

Example 7

4-[6-(3-Piperidin-1-yl-propoxy)-pyridin-3-ylmethyl]-morpholine

This compound is synthesized in a similar fashion as Example 6 usingmorpholine instead of piperidine in step A.

Example 8

2-(4-Piperidin-1-yl-but-1-ynyl)-5-piperidin-1-ylmethyl-pyridine

Step A. Trifluoro-methanesulfonic acid5-piperidin-1-ylmethyl-pyridin-2-yl ester. A solution of6-piperidin-1-ylmethyl-pyridin-3-ol (0.225 g, 1.17 mmol),N-phenyltrifluoromethanesulfonimide (0.50 g, 1.41 mmol), and TEA (0.50mL, 3.50 mmol) in DCM (20 mL) was heated at reflux for 18 h. The solventwas removed and chromatography of the residue (SiO₂: 0-3% 2 M NH₃ inMeOH/DCM) gave the title compound as a solid (0.036 g, 95%).

Step B. 2-(4-Piperidin-1-yl-but-1-ynyl)-5-piperidin-1-ylmethyl-pyridine.To a solution of trifluoro-methanesulfonic acid5-piperidin-1-ylmethyl-pyridin-2-yl ester (0.10 g, 0.31 mmol),1-but-3-ynyl-piperidine (0.051 g, 0.37 mmol), and TEA (2 mL) in dry DMF(1 mL) was added dichlorobis(triphenylphosphine)-palladium(II) (0.004 g,0.006 mmol) and copper(I) iodide (0.004 g, 0.016 mmol). The reactionmixture was heated at 80° C. for 4 h, cooled to rt, diluted with DCM (25mL), and filtered through a pad of diatomaceous earth. The mixture wasdiluted with 1 N NaOH (25 mL) and extracted with DCM (3×25 mL). Theorganic layers were combined, dried (Na₂SO₄), and concentrated, andchromatography of the resulting residue (SiO₂: 3-6% 2 M NH₃ in MeOH/DCM)gave the title compound (0.01 g, 10%). MS (ESI): exact mass calcd. forC₂₀H₂₉N₃, 311.2; m/z found, 312.5 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃): 8.45(d, J=2.0, 1H), 7.62 (d, J=8.3, 1H), 7.25 (d, J=8.1, 1H), 3.47 (s, 2H),2.74-2.70 (m, 4H), 2.62-2.59 (m, 4H), 2.37 (br s, 4H), 1.65-1.55 (m,8H), 1.46-1.44 (m, 4H).

Example 9

(4-Isopropyl-piperazin-1-yl)-[6-(2-piperidin-1-yl-ethylamino)-pyridin-3-yl]-methanone

Step A. (6-Chloro-pyridin-3-yl)-(4-isopropyl-piperazin-1-yl)-methanone.To a solution of 6-chloronicotinic acid (0.985 g, 6.25 mmol) and1-isopropyl-piperazine (1.50 g, 7.50 mmol) in DCM (100 mL) was addedHOBt (1.20 g, 9.40 mmol), EDC (1.80 g, 9.40 mmol), and N-methylmorpholine (3.4 mL, 31.3 mmol). After 18 h the reaction was diluted with1 N NaOH (50 mL) and extracted with DCM (3×50 mL). The organic extractswere combined, dried (Na₂SO₄), and concentrated. Chromatography of theresidue (SiO₂: 2-4% 2 M NH₃ in MeOH/DCM) gave the title compound as asolid (0.934 g, 56%).

Step B.(4-Isopropyl-piperazin-1-yl)-[6-(2-piperidin-1-yl-ethylamino)-pyridin-3-yl]-methanone.A solution of(6-chloro-pyridin-3-yl)-(4-isopropyl-piperazin-1-yl)-methanone (0.20 g,0.75 mmol) and 1-(2-aminoethyl)-piperidine (0.16 mL, 1.13 mmol) in1-butanol (10 mL) was heated at reflux temperature. After 18 h thereaction was concentrated, treated with 1 N aq. NaHCO₃ (25 mL), andextracted with DCM (3×25 mL). The organic layers were combined, dried(Na₂SO₄), and concentrated. Chromatography of the residue (SiO₂: 2-5% 2M NH₃ in MeOH/DCM) gave the title compound as an oil (0.050 g, 20%). MS(ESI): exact mass calcd. for C₂₀H₃₃N₅O, 359.3; m/z found, 360.2 [M+H]⁺.¹H NMR (400 MHz, CDCl₃): 8.20 (d, J=1.8, 1H), 7.54 (dd, J=8.6, 2.3, 1H),6.40 (d, J=9.0, 1H), 5.49 (br s, 1H), 3.65 (br s, 4H), 3.39-3.35 (m,2H), 2.74-2.70 (m, 1H), 2.59-2.57 (m, 2H), 2.53 (br s, 4H), 2.42 (br s,4H), 1.62-1.56 (m, 4H), 1.46-1.45 (m, 2H), 1.04 (d, 6.5, 6H).

Example 10

(4-Isopropyl-piperazin-1-yl)-[6-(2-morpholin-4-yl-ethylamino)-pyridin-3-yl]-methanone

This compound was prepared in a similar fashion as Example 9 using2-morpholin-4-yl-ethylamine in place of 1-(2-aminoethyl)-piperidine instep B. MS (ESI): exact mass calcd. for C₁₉H₃₁N₅O₂, 361.3; m/z found,362.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃): 8.20 (d, J=1.9, 1H), 7.55 (dd,J=8.6, 2.3, 1H), 6.40 (d, J=9.0, 1H), 5.36 (br s, 1H), 3.73-3.71 (m,4H), 3.66-3.62 (m, 4H), 3.41-3.37 (m, 2H), 2.73-2.70 (m, 1H), 2.64-2.60(m, 2H), 2.52-2.47 (m, 8H), 1.04 (d, J=6.5, 6H).

Example 11

(4-Isopropyl-piperazin-1-yl)-[6-(2-pyridin-2-yl-ethylamino)-pyridin-3-yl]-methanone

This compound was prepared in a similar fashion as Example 9 using2-pyridin-2-yl-ethylamine in place of 1-(2-aminoethyl)-piperidine instep B. MS (ESI): exact mass calcd. for C₂₀H₂₇N₅O, 353.46; m/z found,354.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃): 8.57-8.54 (m, 1H), 8.20 (s, 1H),7.63-7.59 (m, 1H), 7.53 (dd, J=8.6, 2.3, 1H), 7.18-7.14 (m, 2H), 6.39(d, J=9.2, 1H), 5.43 (br s, 1H), 3.78-3.73 (m, 2H), 3.65 (br s, 4H),3.10 (t, J=6.5, 2H), 2.74-2.70 (m, 1H), 2.52 (br s, 4H), 1.05 (d, 6.4,6H).

Example 12

{6-[(2-Diethylamino-ethyl)-methyl-amino]-pyridin-3-yl}-(4-isopropyl-piperazin-1-yl)-methanone

This compound was prepared in a similar fashion as Example 9 usingN,N-diethyl-N′-methyl-ethane-1,2-diamine in place of1-(2-aminoethyl)-piperidine in step B. MS (ESI): exact mass calcd. forC₂₀H₃₅N₅O, 361.2; m/z found, 362.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃): 8.26(s, 1H), 7.58 (dd, J=8.8, 2.3, 1H), 6.47 (d, J=9.3, 1H), 3.66-3.63 (m,6H), 3.10 (s, 3H), 2.74-2.71 (m, 1H), 2.64-2.52 (m, 10H), 1.06-1.01 (m,12H).

Example 13

(4-Isopropyl-piperazin-1-yl)-[6-(4-isopropyl-piperazin-1-yl)-pyridin-3-yl]-methanone

This compound was prepared in a similar fashion as Example 9 using1-isopropyl-piperazine in place of 1-(2-aminoethyl)-piperidine in stepB. MS (ESI): exact mass calcd. for C₂₀H₃₃N₅O, 359.5; m/z found, 360.2[M+H]⁺. ¹H NMR (400 MHz, CDCl₃): 8.27 (s, 1H), 7.60 (dd, J=8.8, 2.3,1H), 6.62 (d, J=8.8, 1H), 3.63-3.60 (m, 8H), 2.74-2.70 (m, 2H),2.62-2.60 (m, 4H), 2.53 (br s, 4H), 1.07-1.04 (m, 12H).

Example 14

4-[5-(4-Isopropyl-piperazine-1-carbonyl)-pyridin-2-yl]-piperazine-1-carboxylicacid ethyl ester

This compound was prepared in a similar fashion as Example 9 usingpiperazine-1-carboxylic acid ethyl ester in place of1-(2-aminoethyl)-piperidine in step B. MS (ESI): exact mass calcd. forC₂₀H₃₁N₅O₃, 389.2; m/z found, 390.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃):8.28 (s, 1H), 7.60 (dd, J=8.8, 2.3, 1H), 6.62 (d, J=8.8, 1H), 4.20-4.16(m, 2H), 3.63-3.60 (m, 10H), 2.73 (br s, 1H), 2.54 (br s, 4H), 1.60 (brs, 2H), 1.31-1.28 (m, 3H), 1.06 (d, 6.5, 6H).

Example 15

(4-Isopropyl-piperazin-1-yl)-[6-(4-methyl-piperazin-1-yl)-pyridin-3-yl]-methanone

This compound was prepared in a similar fashion as Example 9 using1-methyl-piperazine in place of 1-(2-aminoethyl)-piperidine in step B.MS (ESI): exact mass calcd. for C₁₈H₂₉N₅O, 331.2; m/z found, 332.2[M+H]⁺. ¹H NMR (400 MHz, CDCl₃): 8.28 (s, 1H), 7.60 (dd, J=8.8, 2.3,1H), 6.62 (d, J=8.8, 1H), 3.63-3.60 (m, 8H), 2.74-2.70 (m, 1H),2.52-2.48 (m, 8H), 2.35 (s, 3H), 1.05 (d, J=6.5, 6H).

Example 16

(4-Isopropyl-piperazin-1-yl)-[2-(2-piperidin-1-yl-ethylamino)-pyridin-4-yl]-methanone

Step A. (2-Chloro-pyridin-4-yl)-(4-isopropyl-piperazin-1-yl)-methanone.The title compound was prepared in a manner similar to that described inStep A of Example 9 using 2-chloro-isonicotinic acid and1-isopropyl-piperazine.

Step B.(4-Isopropyl-piperazin-1-yl)-[2-(2-piperidin-1-yl-ethylamino)-pyridin-4-yl]-methanone.This compound was prepared in a similar fashion as step B in Example 9using (2-chloro-pyridin-4-yl)-piperidin-1-yl-methanone and2-piperidin-1-yl-ethylamine. MS (ESI): exact mass calcd. for C₂₀H₃₃N₅O,359.3; m/z found, 360.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃): 8.11 (d, J=5.1,1H), 6.48 (dd, J=5.1, 1.3, 1H), 6.37 (s, 1H), 5.34 (br s, 1H), 3.75 (brs, 2H), 3.40-3.32 (m, 4H), 2.73-2.71 (m, 1H), 2.59-2.54 (m, 4H),2.45-2.40 (m, 6H), 1.59-1.55 (m, 4H), 1.45-1.44 (m, 2H), 1.05 (d, J=6.5,6H).

Example 17

(4-Isopropyl-piperazin-1-yl)-[2-(2-piperidin-1-yl-ethylamino)-pyridin-3-yl]-methanone

Step A. (2-Chloro-pyridin-3-yl)-(4-isopropyl-piperazin-1-yl)-methanone.The title compound was prepared in a manner similar to that described inStep A of Example 9 using 2-chloro-nicotinic acid and1-isopropyl-piperazine.

Step B.(4-Isopropyl-piperazin-1-yl)-[2-(2-piperidin-1-yl-ethylamino)-pyridin-3-yl]-methanone.This compound was prepared in a similar fashion as step B Example 9using (2-chloro-pyridin-3-yl)-piperidin-1-yl-methanone and2-piperidin-1-yl-ethylamine. MS: exact mass calcd. for C₂₀H₃₃N₅O, 359.3;m/z found, 360.3 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃): 8.11 (d, J=5.1, 1H),6.48 (dd, J=5.1, 1.3, 1H), 6.37 (s, 1H), 5.34 (br s, 1H), 3.75 (br s,2H), 3.40-3.32 (m, 4H), 2.73-2.71 (m, 1H), 2.59-2.54 (m, 4H), 2.45-2.40(m, 6H), 1.59-1.55 (m, 4H), 1.45-1.44 (m, 2H), 1.05 (d, J=6.5, 6H).

Example 18

3-(4-Piperidin-1-yl-but-1-ynyl)-5-piperidin-1-ylmethyl-pyridine

Step A. (5-Bromo-pyridin-3-yl)-methanol. To a solution of5-bromonicotinic acid (20.00 g, 97.00 mmol) in anhydrous THF (250 mL)was added a solution of BH₃ (1 M in THF, 197 mL) slowly at rt over aperiod of 1 h. The reaction mixture was stirred for 1 h at rt and thenwas heated at reflux temperature for 5 h. The reaction mixture wascooled to rt and treated with 1 M HCl (100 mL) drop-wise. The resultingmixture was stirred for 1 h and treated with 10% aq. NaOH until pH 10.The solution was then extracted with ethyl acetate (4×200 mL). Thecombined organic extracts were washed with H₂O, dried over anhydrousNa₂SO₄, filtered and concentrated to yield the crude alcohol (10.71 g).Purification of the crude compound (SiO₂: 0-5% 2 M NH₃ in MeOH/DCM) gave(5-bromo-pyridin-3-yl)-methanol (4.14 g, 22%).

Step B. 5-Bromo-pyridine-3-carbaldehyde. (5-Bromo-pyridin-3-yl)-methanol(1.13 g, 6.00 mmol) was dissolved in CHCl₃ (40 mL) and treated with MnO₂(3.60 g). The reaction mixture was heated at reflux temperature for 3 h.The hot reaction mixture was filtered through a pad of diatomaceousearth and the filtrate was concentrated to yield the title compound(0.570 g, 51%).

Step C. 3-Bromo-5-piperidin-1-ylmethyl-pyridine.5-Bromo-pyridine-3-carbaldehyde (0.190 g, 1 mmol), NaB(OAc)₃H (0.320 g,1.50 mmol) and piperidine (0.090 g, 1.05 mmol) were suspended in DCM (8mL) and the reaction mixture was stirred overnight at rt. The reactionwas quenched by the addition of 1 M NaOH solution (5 mL) and the mixturewas stirred for 1 h. The reaction mixture was extracted with DCM (3×15mL). The organic extracts were combined, dried over Na₂SO₄, filtered,and concentrated to yield a crude oily product (0.18 g, 71%). This crudeproduct was carried to the next step.

Step D.3-(4-Pirperidin-1-yl-but-1-ynyl)-5-piperidin-1-ylmethyl-pyridine.3-Bromo-5-piperidin-1-ylmethyl-pyridine (0.353 g, 1.38 mmol),1-but-3-ynyl-piperidine (0.380 g, 2.77 mmol),dichlorobis(triphenylphosphine)palladium(II) (0.097 g, 0.14 mmol),copper(I) iodide (0.027 g, 0.14 mmol), and Ph₃P (0.131 g, 0.50 mmol)were added to a mixture of DMF (0.50 mL) and Et₂N (3.00 mL) undernitrogen. The system was degassed with vacuum and filled with nitrogenthree times, then heated at 120-125° C. for 2 h. The reaction mixturewas cooled and treated with satd. aq. NaHCO₃ (15 mL) and stirred for 30min. The reaction mixture was extracted with DCM (3×30 mL) and thecombined organic phases washed with H₂O (2×20 mL), dried over anhydrousNa₂SO₄, filtered and concentrated. The residue was purified (SiO₂: 0-7%2 M NH₃ in MeOH/DCM) to yield the title compound (0.018 g, 8%). MS(ESI): exact mass calcd. for C₂₀H₂₉N₃, 311.46; m/z found 312.5 [M+H]⁺.¹H NMR (500 MHz, CDCl₃): 8.48 (d, J=1.9, 1H), 8.39 (d, J=1.6, 1H),7.66-7.64 (m, 1H), 3.42 (s, 2H), 2.69-2.59 (m, 4H), 2.51-2.41 (m, 4H),2.40-2.30 (m, 4H), 1.64-1.51 (m, 8H), 1.48-1.37 (m, 4H).

Example 19

4-[5-(4-Piperidin-1-yl-but-1-ynyl)-pyridin-3-ylmethyl]-morpholine

Step A. 4-(5-Bromo-pyridin-3-ylmethyl)-morpholine. The title compoundwas prepared in a similar way as described in Example 18, Step C, using5-bromo-pyridine-3-carbaldehyde and morpholine. The crude compound waspurified (SiO₂: 0-3% 2 M NH₃ in MeOH/DCM) to provide the title compound(61%).

Step B.4-[5-(4-Piperidin-1-yl-but-1-ynyl)-pyridin-3-ylmethyl]-morpholine. Thiscompound was made in a similar way as described in Example 18, Step D,using 4-(5-bromo-pyridin-3-ylmethyl)-morpholine and1-but-3-ynyl-piperidine (57%). MS (ESI): exact mass calcd. forC₁₉H₂₇N₃O, 313.45; m/z found, 314.5 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃):8.49 (d, J=1.9, 1H), 8.40 (d, J=1.6, 1H), 7.66-7.64 (m, 1H), 3.68 (t,J=4.5, 4H), 3.45 (s, 2H), 2.67-2.58 (m, 4H), 2.49-2.38 (m, 8H),1.62-1.52 (m, 4H), 1.46-1.40 (m, 2H).

Example 20

2-(4-Piperidin-1-yl-but-1-ynyl)-6-piperidin-1-ylmethyl-pyridine

Step A. 6-Bromo-pyridine-2-carbaldehyde. To a −10° C. solution of n-BuLi(2.5 M in hexane, 5.6 mL, 14 mmol) in anhydrous toluene (20 mL) wasadded a solution of n-BuMgCl (2 M in THF, 3.5 mL) over 20 min,maintaining the temperature between −10° C. and 0° C. The mixture wasstirred at −10° C. for 30 min. A solution of 2,6-dibromo-pyridine (4.74g, 20 mmol) in toluene (20 mL) was added drop-wise over a period of 30min while keeping the temperature below −5° C. The resulting suspensionwas stirred at −10° C. for 2.5 h. The mixture was transferred viacannula to a −10° C. solution of DMF (1.9 g, 26 mmol) in toluene (10mL). The solution was allowed to stand between −5° C. and −10° C. for 30min and then was transferred into a solution of citric acid (8.00 g) inH₂O (15 mL), maintaining the temperature below 20° C. The resultingsolution was stirred for 10 min and the layers were separated. Theorganic layer was dried over Na₂SO₄, filtered, and concentrated. Theresidue was purified (SiO₂: 10% ethyl acetate/hexanes) to afford thetitle compound (1.94 g, 52%).

Step B. 2-Bromo-6-piperidin-1-ylmethyl-pyridine. The title compound wasprepared in a manner similar to that described in Example 18, Step C,using 6-bromo-pyridine-2-carbaldehyde (0.406 g, 2.18 mmol) andpiperidine (0.186 g, 2.18 mmol). The crude product was purified (SiO₂:0-4% 2 M NH₃ in MeOH/DCM) to provide the title compound (0.46 g, 83%).

Step C.2-(4-Pirperidin-1-yl-but-1-ynyl)-6-piperidin-1-ylmethyl-pyridine. Thetitle compound was prepared in a manner similar to that described inExample 18, Step D, using 2-bromo-6-piperidin-1-ylmethyl-pyridine and1-but-3-ynyl-piperidine (56%). MS (ESI): exact mass calcd. for C₂₀H₂₉N₃,311.46; m/z found, 312.5 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃): 7.54 (t,J=7.7, 1H), 7.38 (d, J=7.7, 1H), 7.20 (d, J=7.4, 1H), 3.58 (s, 2H),2.67-2.57 (m, 4H), 2.46-2.34 (m, 8H), 1.60-1.50 (m, 8H), 1.44-1.36 (m,4H).

Example 21

4-[6-(4-Piperidin-1-yl-but-1-ynyl)-pyridin-2-ylmethyl]-morpholine

Step A. 4-(6-Bromo-pyridin-2-ylmethyl)-morpholine. The title compoundwas prepared in a manner similar to that described in Example 18, StepC, using 6-bromo-pyridine-2-carbaldehyde (0.415 g, 2.23 mmol) andmorpholine (0.195 g, 2.23 mmol). The crude product was purified (SiO₂:0-3% 2 M NH₃ in MeOH/DCM) to give the title compound (0.352 g, 61%).

Step B.4-[6-(4-Piperidin-1-yl-but-1-ynyl)-pyridin-2-ylmethyl]-morpholine. Thetitle compound (19%) was prepared in a manner similar to that describedin Example 18, Step D, using 4-(6-bromo-pyridin-2-ylmethyl)-morpholine(0.278 g, 1.08 mmol) and 1-but-3-ynyl-piperidine (0.297 g, 2.16 mmol).MS (ESI): exact mass calcd. for C₁₉H₂₇N₃O, 313.45; m/z found, 314.4[M+H]⁺. ¹H NMR (500 MHz, CDCl₃): 7.52 (t, J=7.8, 1H), 7.32 (dd, J=8.0,1.1, 1H), 7.20 (dd, J=7.1, 1.1, 1H), 3.65 (t, J=4.6, 4H), 3.58 (s, 2H),2.65-2.55 (m, 4H), 2.46-2.37 (m, 8H), 1.57-1.49 (m, 4H), 1.41-1.34 (m,2H).

Example 22

(2-Methoxy-ethyl)-[6-(4-piperidin-1-yl-but-1-ynyl)-pyridin-2-ylmethyl]-amine

Step A. (6-Bromo-pyridin-2-ylmethyl)-(2-methoxy-ethyl)-amine. The titlecompound was prepared in a manner similar to that described in Example18, Step C, using 6-bromo-pyridine-2-carbaldehyde (0.275 g, 1.48 mmol)and 2-methoxy-ethylamine (0.111 g, 1.48 mmol). The crude product waspurified (SiO₂: 0-5% MeOH/DCM) to yield the title compound (0.34 g,94%).

Step B.(2-Methoxy-ethyl)-[6-(4-piperidin-1-yl-but-1-ynyl)-pyridin-2-ylmethyl]-amine.The title compound (13%) was prepared in a manner similar to thatdescribed in Example 18, Step D, using(6-bromo-pyridin-2-ylmethyl)-(2-methoxy-ethyl)-amine (0.300 g, 1.23mmol) and 1-but-3-ynyl-piperidine (0.336 g, 2.45 mmol). MS (ESI): exactmass calcd. for C₁₈H₂₇N₃O, 301.44; m/z found, 302.4 [M+H]⁺. ¹H NMR (500MHz, CDCl₃): 7.56 (t, 7.7, 1H), 7.26 (d, J=7.1, 1H), 7.23 (d, J=7.7,1H), 3.90 (s, 2H), 3.52-3.45 (m, 2H), 3.34 (s, 3H), 2.80 (t, J=5.2, 2H),2.70-2.59 (m, 4H), 2.48-2.40 (m, 4H), 1.67-1.54 (m, 5H), 1.46-1.38 (m,2H).

Example 23

(4-Isopropyl-piperazin-1-yl)-(5-piperidin-1-ylmethyl-pyrazin-2-yl)-methanone

Step A. 5-Dibromomethyl-pyrazine-2-carboxylic acid methyl ester.5-Methyl-pyrazine-2-carboxylic acid methyl ester (1.60 g, 10.5 mmol;Macdonald, S. J. F. et al. J. Med. Chem. 2002, 45(18):3878-3890.),N-bromosuccinimide (5.62 g, 31.6 mmol), and dibenzoyl peroxide (0.255 g,1.05 mmol) were dissolved in CCl₄ (80 mL). The mixture was heated atreflux for 18 h. The reaction mixture was cooled and washed with 10% aq.Na₂SO₃ (2×20 mL) and H₂O (1×30 mL). The organic phase was dried overNa₂SO₄, filtered, and concentrated to yield a brown oily crude material(2.41 g). The crude product was purified (SiO₂: 0-20% ethylacetate/hexanes) to give the title compound (1.00 g, 31%).

Step B. 5-Formyl-pyrazine-2-carboxylic acid methyl ester. A solution of5-dibromomethyl-pyrazine-2-carboxylic acid methyl ester (1.00 g, 3.23mmol) in a mixture of ethanol (20 mL) and THF (10 mL) was heated to 80°C. A solution of silver nitrate (2.20 g, 12.9 mmol) in H₂O (4 mL) wasadded. The reaction mixture was heated at 80° C. for 1.25 h and wasfiltered while hot. The filtrate was concentrated to yield the titlecompound (1.36 g). This material was carried to the next step withoutpurification.

Step C. 5-Piperidin-1-ylmethyl-pyrazine-2-carboxylic acid methyl ester.A mixture of 5-formyl-pyrazine-2-carboxylic acid methyl ester (0.400 g,2.40 mmol), piperidine (0.204 g, 2.40 mmol), and NaB(OAc)₃H (1.40 g,3.60 mmol) in DCM (10 mL) was stirred for 18 h at rt. The reaction wasquenched by the addition of 10% aq. NaOH (10 mL) and the mixture wasstirred for 30 min. The mixture was extracted with DCM (3×20 mL). Thecombined organic extracts were dried over Na₂SO₄, filtered, andconcentrated to yield the title compound (0.130 g, 23%).

Step D. 5-Piperidin-1-ylmethyl-pyrazine-2-carboxylic acid. A mixture of5-piperidin-1-ylmethyl-pyrazine-2-carboxylic acid methyl ester (0.125 g,0.53 mmol) in dioxane (3 mL) was treated with 1 M aq. LiOH (0.53 mL,0.53 mmol) and stirred for 18 h. The mixture was concentrated to yieldthe crude lithium salt of the acid (0.120 g).

Step E.(4-Isopropyl-piperazin-1-yl)-(5-piperidin-1-ylmethyl-pyrazin-2-yl)-methanone.A mixture of 5-piperidin-1-ylmethyl-pyrazine-2-carboxylic acid (0.125 g,0.53 mmol), 1-isopropyl-piperazine dihydrochloride (0.117 g, 0.58 mmol),HOBt (0.086 g, 0.64 mmol) and N-methylmorpholine (0.323 g, 3.19 mmol) inDCM (7 mL) was stirred for 1 h. The mixture was then treated with EDC(0.122 g, 0.64 mmol) and stirring was continued for 18 h. The reactionwas quenched by the addition of 1 N NaOH (10 mL), and was stirred for 30min. The mixture was diluted with H₂O (10 mL) and extracted with DCM(3×15 mL). The combined organic layers were dried over Na₂SO₄, filtered,and concentrated to yield the crude product (0.145 g). The crude waspurified on SiO₂ using 0-5% 2 M NH₃ in MeOH/DCM to provide the titlecompound (0.05 g, 26%). MS (ESI): exact mass calcd. for C₁₈H₂₉N₅O,331.46; m/z found 332.5 [M+H]⁺. ¹HNMR (500 MHz, CDCl₃): 8.85 (d, J=1.4,1H), 8.64 (d, J=1.4, 1H), 3.82 (t, J=4.9, 2H), 3.68 (s, 2H), 3.63 (t,J=4.9, 2H), 2.77-2.70 (m, 1H), 2.62 (t, J=4.9, 2H), 2.53 (t, J=4.9, 2H),2.48-2.42 (m, 4H), 1.63-1.57 (m, 4H), 1.49-1.42 (m, 2H), 1.05 (d, J=6.6,6H).

Example 24

(4-Isopropyl-piperazin-1-yl)-(5-morpholin-4-ylmethyl-pyrazin-2-yl)-methanone

Step A. 5-Morpholin-4-ylmethyl-pyrazine-2-carboxylic acid methyl ester.The title compound was prepared in a manner similar to that described inExample 23, Step C, using 5-formyl-pyrazine-2-carboxylic acid methylester (0.78 g, 4.7 mmol) and morpholine (0.44 g, 5.2 mmol).

Step B. 5-Morpholin-4-ylmethyl-pyrazine-2-carboxylic acid. Hydrolysis of5-morpholin-4-ylmethyl-pyrazine-2-carboxylic acid methyl ester (0.28 g)was performed in a similar manner to that described in Example 23, StepD, to give the crude lithium salt of the acid (0.224 g).

Step C.(4-Isopropyl-piperazin-1-yl)-(5-morpholin-4-ylmethyl-pyrazin-2-yl)-methanone.The title compound (0.022 g, 7%) was prepared in a manner similar tothat described in Example 23, Step E. MS (ESI): exact mass calcd. forC₁₇H₂₇N₅O, 333.44; m/z found 334.5 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃): 8.87(d, J=1.4, 1H), 8.64 (d, J=1.4, 1H), 3.84-3.79 (m, 2H), 3.76-3.71 (m,6H), 3.63-3.59 (m, 2H), 2.77-2.71 (m, 1H), 2.64-2.60 (m, 2H), 2.55-2.44(m, 6H), 1.05 (d, J=6.6, 6H).

Example 25

4-[3-(3-Piperidin-1-yl-propoxy)-isoxazol-5-ylmethyl]-piperidine

Step A. 3-(3-Piperidin-1-yl-propoxy)-isoxazole-5-carboxylic acid methylester. 3-Hydroxy-isoxazole-5-carboxylic acid methyl ester (0.859 g.,6.00 mmol) and 3-piperidin-1-yl-propan-1-ol (0.860 g., 6.00 mmol) weredissolved in DCM (30 mL), and polymer-supported Ph₃P resin (3 mmol/g,3.1 g, 9.30 mmol) was added. The mixture was stirred for 10 min anddi-tert-butyl azodicarboxylate (2.14 g, 9.30 mmol) was then added. Thereaction mixture was stirred under nitrogen for 18 h. The reaction wasquenched with 1 N NaOH (20 mL) and was stirred for 30 min. The resultingmixture was extracted with DCM (3×30 mL). The combined organic extractswere dried over Na₂SO₄, filtered, and concentrated to yield a crude oilyproduct (3.1 g), which was purified (SiO₂: 5% 2 M NH₃ in MeOH/DCM) toyield the title compound (0.88 g, 58%). MS (ESI): exact mass calcd. forC₁₃H₂₀N₂O₄, 268.14; m/z found, 269.4 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃):6.53 (s, 1H), 4.34-4.30 (m, 2H), 3.94 (s, 3H), 2.47-2.34 (m, 6H),2.02-1.94 (m, 2H), 1.61-1.54 (m, 4H), 1.47-1.39 (m, 2H).

Step B. [3-(3-Piperidin-1-yl-propoxy)-isoxazol-5-yl]-methanol. To asolution of 3-(3-piperidin-1-yl-propoxy)-isoxazole-5-carboxylic acidmethyl ester (0.200 g, 0.750 mmol) in EtOH (15 mL) was added NaBH₄(0.358 g, 11.2 mmol) was slowly over 30 min. The reaction mixture washeated at reflux overnight, then was cooled to rt and quenched by theaddition of 1 N NaOH (10 mL). The mixture was stirred for 1 h, and thenwas extracted with DCM (3×30 mL). The combined organic extracts weredried over Na₂SO₄, filtered, and concentrated to yield the desiredalcohol (0.177 g, 99%). MS (ESI): exact mass calcd. for C₁₂H₂₀N₂O₃,240.15; m/z found, 241.3 [M+H]⁺.

Step C. 1-[3-(5-Chloromethyl-isoxazol-3-yloxy)-propyl]-piperidine. Amixture of [3-(3-piperidin-1-yl-propoxy)-isoxazol-5-yl]-methanol (0.150g, 0.625 mmol) and neat thionyl chloride (4 mL) was heated at reflux for3 h. The reaction mixture was cooled to rt and concentrated to give thedesired chloride, which was carried to the next step without furtherpurification.

Step D. 4-[3-(3-Piperidin-1-yl-propoxy)-isoxazol-5-ylmethyl]-piperidine.1-[3-(5-Chloromethyl-isoxazol-3-yloxy)-propyl]-piperidine (0.15 g, 0.80mmol) was dissolved in DCM (5 mL) and piperidine (0.24 mL, 2.4 mmol) wasadded slowly. The reaction mixture was stirred overnight at rt and thenwas concentrated to yield the crude product (0.140 g). The crude productwas purified (SiO₂: 0-5% 2 M NH₃ in MeOH/DCM) to give the final product(0.118 g, 47.6%). MS (ESI): exact mass calcd. for C₁₇H₂₉N₃O₂, 307.23;m/z found 308.4 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃): 5.75 (s, 1H), 4.25-4.20(m, 2H), 3.53 (s, 2H), 2.47-2.31 (m, 10H), 1.98-1.90 (m, 2H), 1.61-1.52(m, 8H), 1.45-1.35 (m, 4H).

Example 26

4-[3-(3-Piperidin-1-yl-propoxy)-isoxazol-5-ylmethyl]-morpholine

The title compound was prepared in a manner similar to that described inExample 25, Step D. MS (ESI): exact mass calcd. for C₁₆H₂₇N₃O₃, 309.21;m/z found, 310.5 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃): 5.80 (s, 1H),4.27-4.21 (m, 2H), 3.70 (t, J=4.7, 4H), 3.54 (s, 2H), 2.53-2.32 (m,10H), 2.00-1.92 (m, 2H), 1.61-1.54 (m, 4H), 1.46-1.38 (m, 2H).

Example 27

(2-Methoxy-ethyl)-[3-(3-piperidin-1-yl-propoxy)-isoxazol-5-ylmethyl]-amine

The title compound was prepared in a manner similar to that described inExample 25, Step D. MS (ESI): exact mass calcd. for C₁₅H₂₇N₃O₃, 297.21;m/z found, 298.5 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃): 5.78 (s, 1H),4.26-4.22 (m, 2H), 3.81 (br s, 2H), 3.50-3.46 (m, 2H), 3.35 (s, 3H),2.82-2.79 (m, 2H), 2.45-2.40 (m, 2H), 2.40-2.33 (m, 3H), 1.99-1.92 (m,2H), 1.87-1.76 (m, 2H), 1.60-1.54 (m, 4H), 1.46-1.39 (m, 2H).

Example 28

(4-Isopropyl-piperazin-1-yl)-(6-piperidin-1-ylmethyl-pyridin-3-yl)-methanethione

A solution of(4-isopropyl-piperazin-1-yl)-(6-piperidin-1-ylmethyl-pyridin-3-yl)-methanone(Example 1, 80 mg, 0.24 mmol) and Lawesson's reagent (210 mg, 0.50 mmol)in THF was heated at reflux for 48 h. The reaction was cooled to rt andthe solvent was removed in vacuo. Chromatography of the residue (SiO₂:1-6% 2 M NH₃ in MeOH/DCM) gave the title compound as an oil. MS (ESI):exact mass calcd. for C₁₉H₃₀N₄S, 346.22; m/z found, 347.5 [M+H]⁺.

Biology Example A. Transfection of Cells with Human Histamine Receptor

Cells were grown to about 70% to 80% confluence and removed from theplate with trypsin and pelleted in a clinical centrifuge. The pellet wasthen re-suspended in 400 μL of complete media and transferred to anelectroporation cuvette with a 0.4 cm gap between the electrodes(Bio-Rad #165-2088). One μg supercoiled H₃ receptor cDNA was added tothe cells and mixed gently. The voltage for the electroporation was setat 0.25 kV and the capacitance was set at 960 μF. After electroporationthe cells were diluted with 10 mL of complete media and were plated ontofour 10 cm dishes at the following ratios: 1:20, 1:10, 1:5, and 1:2. Thecells were allowed to recover for 24 h before adding 600 μg G-418.Colonies that survived selection were grown and tested. SK-N-MC cellswere used because they give efficient coupling for inhibition ofadenylate cyclase. The clones that gave the most robust inhibition ofadenylate cyclase in response to histamine were used for further study.

B. [³H]-N-Methylhistamine Binding

Cell pellets from histamine H₃ receptor-expressing SK-N-MC cells werehomogenized in 50 mM Tris HCl/0.5 mM EDTA. Supernatants from an 800 gspin were collected and were recentrifuged at 30,000 g for 30 min.Pellets were re-homogenized in 50 mM Tris/5 mM EDTA (pH 7.4). Membraneswere incubated with 0.8 nM [³H]-N-methylhistamine plus/minus testcompounds for 60 min at 25° C. and were harvested by rapid filtrationover GF/C glass fiber filters (pretreated with 0.3% polyethylenimine)followed by four washes with buffer. Filters were added to 5 mL ofscintillation cocktail, and the signal was then counted on a liquidscintillation counter. Non-specific binding was defined with 10 μMhistamine. pK_(i) values were calculated based on a K_(D) of 0.8 nM anda ligand concentration ([L]) of 0.8 nM according to the formulaK_(i)=(IC₅₀)/(1+([L]/(KD)). Data are presented in Table 1.

TABLE 1 Biological Data. EX K_(i) (nM)  1 1  2 18  3 2  4 0.8  5 13  8 5 9 2 10 14 11 84 12 3 13 4 14 79 15 3 16 6 17 141 18 2 19 15 20 8 21 3822 29 23 2 24 39 25 7 26 89 27 169 28 7

1.-44. (canceled)
 45. A method for the treatment or prevention of a CNS disorder selected from the group consisting of: neurologic disorders including sleep/wake and arousal/vigilance disorders (e.g. insomnia and jet lag), attention deficit hyperactivity disorders (ADHD), learning and memory disorders, cognitive dysfunction, migraine, neurogenic inflammation, dementia, mild cognitive impairment (pre-dementia), Alzheimer's disease, epilepsy, narcolepsy with or without associated cataplexy, cataplexy, disorders of sleep/wake homeostasis, idiopathic somnolence, excessive daytime sleepiness (EDS), circadian rhythm disorders, sleep/fatigue disorders, fatigue, drowsiness associated with sleep apnea, sleep impairment due to perimenopausal hormonal shifts, Parkinson's-related fatigue, MS-related fatigue, depression-related fatigue, chemotherapy-induced fatigue, eating disorders, obesity, motion sickness, vertigo, schizophrenia, substance abuse, bipolar disorders, manic disorders and depression in mammals, comprising the step of administering to a mammal suffering there from a therapeutically effective amount of compound having histamine H3 receptor modulator activity of formula (I):

wherein in the A- and B-containing ring, I) A, B¹ and B² are CH; II) A is CH, one of B¹ and B² is N, and the other of B¹ and B² is CH; or III) A is absent, B¹ is CH, and B² is O; L is —C₁₋₄alkylene- or a covalent bond; Q is —(CH₂)_(m)O—, —(CH₂)_(n)C—C— (where the O— and —C≡C— portions are directly attached to the ring), carbonyl, or thiocarbonyl; m is 2, 3, or 4; n is 1, 2, 3, or 4; R¹, optionally mono- or di-substituted with R^(p), is independently selected from the group consisting of —H, —C₁₋₇alkyl, —C₂₋₇alkenyl, —C₂₋₇alkynyl, —C₃₋₇cycloalkyl, phenyl, benzyl, pyridinyl, pyrimidinyl, furanyl, thienyl, pyrrolyl, and a 5-, 6-, or 7-membered monocyclic non-aromatic heterocyclic ring having 1 or 2 heteroatom members selected from O, S, —N═, >NH, and >NC₁₋₄alkyl, having 0, 1, or 2 double bonds; R², optionally mono- or di-substituted with R^(p), is independently selected from the group consisting of —C₁₋₇alkyl, —C₂₋₇alkenyl, —C₂₋₇alkynyl, —C₃₋₇cycloalkyl, phenyl, benzyl, pyridinyl, pyrimidinyl, furanyl, thienyl, pyrrolyl, and a 5-, 6-, or 7-membered monocyclic non-aromatic heterocyclic ring having 1 or 2 heteroatom members selected from O, S, —N═, >NH, and >NC₁₋₄alkyl, having 0, 1, or 2 double bonds; or, alternatively, R¹ and R² may be taken together with the nitrogen of attachment to form a ring, said ring selected from the group consisting of: i) a 4-7 membered non-aromatic heterocyclic ring, said heterocyclic ring having 0 or 1 additional heteroatom members separated from the nitrogen of attachment by at least one carbon member and selected from O, S, —N═, >NH, and >NC₁₋₄alkyl, having 0, 1, or 2 double bonds, having 0, 1, or 2 carbon members which is a carbonyl, having 0, 1, or 2 substituents Rq; and ii) a benzo or pyrido fused 4-7 membered non-aromatic heterocyclic ring, said heterocyclic ring having 0 or 1 additional heteroatom members separated from the nitrogen of attachment by at least one carbon member and selected from O, S, —N═, >NH, and >NC₁₋₄alkyl, having 0 or 1 additional double bonds, having 0, 1, or 2 carbon members which is a carbonyl, and having 0, 1, or 2 substituents R^(q); R^(p) is independently selected from the group consisting of —C₁₋₆alkyl, —C₂₋₆alkenyl, —C₃₋₆cycloalkyl, phenyl, pyridyl, furanyl, thienyl, benzyl, pyrimidinyl, pyrrolyl, halo, —OH, —OC₁₋₆alkyl, —OC₃₋₆cycloalkyl, —Ophenyl, —Obenzyl, —SH, —SC₁₋₆alkyl, —SC₃₋₆cycloalkyl, —Sphenyl, —Sbenzyl, —CN, —NO₂, —N(R^(y))R^(z) (wherein R^(y) and R^(z) are independently selected from H and C₁₋₄alkyl; or R^(y) and R^(z) may be taken together with the nitrogen of attachment to form a 5-, 6-, or 7-membered monocyclic heterocyclic ring having 1 or 2 additional heteroatom members selected from O, S, —N═, >NH, and >NC₁₋₄alkyl, said ring optionally substituted with —C₁₋₄alkyl, —OH, —OC₁₋₄alkyl, halo, or —COOC₁₋₄alkyl), —(C═O)N(R^(y))R^(z), —(C═O)C₁₋₄alkyl, —SCF₃, —OCF₃, —CF₃, and —COOC₁₋₄alkyl, and —COOH; R^(q) is independently selected from the group consisting of —C₁₋₆alkyl, halo, —OH, —OC₁₋₆alkyl, —CN, —NO₂, —CF₃, and —COOC₁₋₄alkyl, R³, optionally mono- or di-substituted with R⁵, is independently selected from the group consisting of —H, —C₁₋₇alkyl, —C₂₋₇alkenyl, —C₂₋₇alkynyl, —C₃₋₇cycloalkyl, phenyl, benzyl, pyridinyl, pyrimidinyl, furanyl, thienyl, pyrrolyl, and a 5-, 6-, or 7-membered monocyclic non-aromatic heterocyclic ring having 1 or 2 heteroatom members selected from O, S, —N═, >NH, and >NC₁₋₄alkyl, having 0, 1, or 2 double bonds; and R⁴, optionally mono- or di-substituted with R^(s), is independently selected from the group consisting of —C₁₋₇alkyl, —C₂₋₇alkenyl, —C₂₋₇alkynyl, —C₃₋₇cycloalkyl, phenyl, benzyl, pyridinyl, pyrimidinyl, furanyl, thienyl, pyrrolyl, and a 5-, 6-, or 7-membered monocyclic non-aromatic heterocyclic ring having 1 or 2 heteroatom members selected from O, S, —N═, >NH, and >NC₁₋₄alkyl, having 0, 1, or 2 double bonds; R^(s) is independently selected from the group consisting of —C₁₋₆alkyl, —C₂₋₆alkenyl, —C₃₋₆cycloalkyl, phenyl, pyridyl, furanyl, thienyl, benzyl, pyrimidinyl, pyrrolyl, halo, —OH, —OC₁₋₆alkyl, —OC₃₋₆cycloalkyl, —Ophenyl, —Obenzyl, —SH, —SC₁₋₆alkyl, —SC₃₋₆cycloalkyl, —Sphenyl, —Sbenzyl, —CN, —NO₂, —N(R^(y))R^(z) (wherein R^(y) and R^(z) are independently selected from H and C₁₋₄alkyl; or R^(y) and R^(z) may be taken together with the nitrogen of attachment to form a 5-, 6-, or 7-membered monocyclic heterocyclic ring having 1 or 2 additional heteroatom members selected from O, S, —N═, >NH, and >NC₁₋₄alkyl, said ring optionally substituted with —C₁₋₄alkyl, —OH, —OC₁₋₄alkyl, halo, or —COOC₁₋₄alkyl), —(C═O)N(R^(y))R^(z), —(C═O)C₁₋₄alkyl, —SCF₃, —OCF₃, —CF₃, —COOC₁₋₄alkyl, and —COOH; or, alternatively R³ and R⁴ may be taken together with the nitrogen of attachment to form a ring, said ring selected from the group consisting of: i) a 4-7 membered non-aromatic heterocyclic ring said heterocyclic ring having 0 or 1 additional heteroatom members separated from the nitrogen of attachment by at least one carbon member and selected from O, S, —N═, >NH, and >NC₁₋₄alkyl, having 0, 1, or 2 double bonds, having 0, 1, or 2 carbon members which is a carbonyl, having 0, 1, or 2 substituents Rt; and ii) a benzo or pyrido fused 4-7 membered non-aromatic heterocyclic ring said heterocyclic ring having 0 or 1 additional heteroatom members separated from the nitrogen of attachment by at least one carbon member and selected from O, S, —N═, >NH, and >NC₁₋₄alkyl, having 0 or 1 additional double bonds, having 0, 1, or 2 carbon members which is a carbonyl, and having 0, 1, or 2 substituents Rt; R^(t) is independently selected from the group consisting of is independently selected from the group consisting of —C₁₋₆alkyl, halo, —OH, —OC₁₋₆alkyl, —CN, —NO₂, —CF₃, and —COOC₁₋₄alkyl; and enantiomers, diastereomers, hydrates, solvates and pharmaceutically acceptable salts, esters and amides thereof.
 46. A method for the treatment or prevention of a histamine H₃ receptor mediated disorder selected from the group consisting of upper airway allergic response, asthma, itch, nasal congestion and allergic rhinitis in mammals, comprising the step of administering to a mammal suffering there from a therapeutically effective amount of compound having histamine H₃ receptor modulator activity of formula (I):

wherein in the A- and B-containing ring, I) A, B¹ and B² are CH; II) A is CH, one of B¹ and B² is N, and the other of B¹ and B² is CH; or III) A is absent, B¹ is CH, and B² is O; L is —C₁₋₄alkylene- or a covalent bond; Q is —(CH₂)_(m)O—, —(CH₂)_(n)C≡C— (where the —O— and —C≡C— portions are directly attached to the ring), carbonyl, or thiocarbonyl; m is 2, 3, or 4; n is 1, 2, 3, or 4; R¹, optionally mono- or di-substituted with R^(p), is independently selected from the group consisting of —H, —C₁₋₇alkyl, —C₂₋₇alkenyl, —C₂₋₇alkynyl, —C₃₋₇cycloalkyl, phenyl, benzyl, pyridinyl, pyrimidinyl, furanyl, thienyl, pyrrolyl, and a 5-, 6-, or 7-membered monocyclic non-aromatic heterocyclic ring having 1 or 2 heteroatom members selected from O, S, —N═, >NH, and >NC₁₋₄alkyl, having 0, 1, or 2 double bonds; R², optionally mono- or di-substituted with R^(p), is independently selected from the group consisting of —C₁₋₇alkyl, —C₂₋₇alkenyl, —C₂₋₇alkynyl, —C₃₋₇cycloalkyl, phenyl, benzyl, pyridinyl, pyrimidinyl, furanyl, thienyl, pyrrolyl, and a 5-, 6-, or 7-membered monocyclic non-aromatic heterocyclic ring having 1 or 2 heteroatom members selected from O, S, —N═, >NH, and >NC₁₋₄alkyl, having 0, 1, or 2 double bonds; or, alternatively, R¹ and R² may be taken together with the nitrogen of attachment to form a ring, said ring selected from the group consisting of: i) a 4-7 membered non-aromatic heterocyclic ring, said heterocyclic ring having 0 or 1 additional heteroatom members separated from the nitrogen of attachment by at least one carbon member and selected from O, S, —N═, >NH, and >NC₁₋₄alkyl, having 0, 1, or 2 double bonds, having 0, 1, or 2 carbon members which is a carbonyl, having 0, 1, or 2 substituents R^(q); and ii) a benzo or pyrido fused 4-7 membered non-aromatic heterocyclic ring, said heterocyclic ring having 0 or 1 additional heteroatom members separated from the nitrogen of attachment by at least one carbon member and selected from O, S, —N═, >NH, and >NC₁₋₄alkyl, having 0 or 1 additional double bonds, having 0, 1, or 2 carbon members which is a carbonyl, and having 0, 1, or 2 substituents R^(q); R^(p) is independently selected from the group consisting of —C₁₋₆alkyl, —C₂₋₆alkenyl, —C₃₋₆cycloalkyl, phenyl, pyridyl, furanyl, thienyl, benzyl, pyrimidinyl, pyrrolyl, halo, —OH, —OC₁₋₆alkyl, —OC₃₋₆cycloalkyl, —Ophenyl, —Obenzyl, —SH, —SC₁₋₆alkyl, —SC₃₋₆cycloalkyl, —Sphenyl, —Sbenzyl, —CN, —NO₂, —N(R^(y))R^(z) (wherein R^(y) and R^(z) are independently selected from H and C₁₋₄alkyl; or R^(y) and R^(z) may be taken together with the nitrogen of attachment to form a 5-, 6-, or 7-membered monocyclic heterocyclic ring having 1 or 2 additional heteroatom members selected from O, S, —N═, >NH, and >NC₁₋₄alkyl, said ring optionally substituted with —C₁₋₄alkyl, —OH, —OC₁₋₄alkyl, halo, or —COOC₁₋₄alkyl), —(C═O)N(R^(y))R^(z), —(C═O)C₁₋₄alkyl, —SCF₃, —OCF₃, —CF₃, and —COOC₁₋₄alkyl, and —COOH; R^(q) is independently selected from the group consisting of —C₁₋₆alkyl, halo, —OH, —OC₁₋₆alkyl, —CN, —NO₂, —CF₃, and —COOC₁₋₄alkyl, R³, optionally mono- or di-substituted with KS, is independently selected from the group consisting of —H, —C₁₋₇alkyl, —C₂₋₇alkenyl, —C₂₋₇alkynyl, —C₃₋₇cycloalkyl, phenyl, benzyl, pyridinyl, pyrimidinyl, furanyl, thienyl, pyrrolyl, and a 5-, 6-, or 7-membered monocyclic non-aromatic heterocyclic ring having 1 or 2 heteroatom members selected from O, S, —N═, >NH, and >NC₁₋₄alkyl, having 0, 1, or 2 double bonds; and R⁴, optionally mono- or di-substituted with R^(s), is independently selected from the group consisting of —C₁₋₇alkyl, —C₂₋₇alkenyl, —C₂₋₇alkynyl, —C₃₋₇cycloalkyl, phenyl, benzyl, pyridinyl, pyrimidinyl, furanyl, thienyl, pyrrolyl, and a 5-, 6-, or 7-membered monocyclic non-aromatic heterocyclic ring having 1 or 2 heteroatom members selected from O, S, —N═, >NH, and >NC₁₋₄alkyl, having 0, 1, or 2 double bonds; R^(s) is independently selected from the group consisting of —C₁₋₆alkyl, —C₂₋₆alkenyl, —C₃₋₆cycloalkyl, phenyl, pyridyl, furanyl, thienyl, benzyl, pyrimidinyl, pyrrolyl, halo, —OH, —OC₁₋₆alkyl, —OC₃₋₆cycloalkyl, —Ophenyl, —Obenzyl, —SH, —SC₁₋₆alkyl, —SC₃₋₆cycloalkyl, —Sphenyl, —Sbenzyl, —CN, —NO₂, —N(R^(y))R^(z) (wherein R^(y) and R^(z) are independently selected from H and C₁₋₄alkyl; or R^(y) and R^(z) may be taken together with the nitrogen of attachment to form a 5-, 6-, or 7-membered monocyclic heterocyclic ring having 1 or 2 additional heteroatom members selected from O, S, —N═, >NH, and >NC₁₋₄alkyl, said ring optionally substituted with —C₁₋₄alkyl, —OH, —OC₁₋₄alkyl, halo, or —COOC₁₋₄alkyl), —(C═O)N(R^(y))R^(z), —(C═O)C₁₋₄alkyl, —SCF₃, —OCF₃, —CF₃, —COOC₁₋₄alkyl, and —COOH; or, alternatively R³ and R⁴ may be taken together with the nitrogen of attachment to form a ring, said ring selected from the group consisting of: i) a 4-7 membered non-aromatic heterocyclic ring said heterocyclic ring having 0 or 1 additional heteroatom members separated from the nitrogen of attachment by at least one carbon member and selected from O, S, —N═, >NH, and >NC₁₋₄alkyl, having 0, 1, or 2 double bonds, having 0, 1, or 2 carbon members which is a carbonyl, having 0, 1, or 2 substituents Rt; and ii) a benzo or pyrido fused 4-7 membered non-aromatic heterocyclic ring said heterocyclic ring having 0 or 1 additional heteroatom members separated from the nitrogen of attachment by at least one carbon member and selected from O, S, —N═, >NH, and >NC₁₋₄alkyl, having 0 or 1 additional double bonds, having 0, 1, or 2 carbon members which is a carbonyl, and having 0, 1, or 2 substituents R^(t); R^(t) is independently selected from the group consisting of is independently selected from the group consisting of —C₁₋₆alkyl, halo, —OH, —OC₁₋₆alkyl, —CN, —NO₂, —CF₃, and —COOC₁₋₄alkyl; and enantiomers, diastereomers, hydrates, solvates and pharmaceutically acceptable salts, esters and amides thereof. 47.-48. (canceled)
 49. A method for treating allergic rhinitis, nasal congestion, or allergic congestion, comprising (a) administering to the subject a jointly effective amount of a compound of formula (1)

wherein in the A- and B-containing ring, I) A, B¹ and B² are CH; II) A is CH, one of B¹ and B² is N, and the other of B¹ and B² is CH; or III) A is absent B¹ is CH, and B² is O; L is —C₁₋₄alkylene- or a covalent bond; Q is —(CH₂)_(m)O—, —(CH₂)_(n)C≡C— (where the —O— and —C≡C— portions are directly attached to the ring) carbonyl or thiocarbonyl: m is 2, 3, or 4; n is 1, 2, 3, or 4; R¹, optionally mono- or di-substituted with R^(p), is independently selected from the group consisting of —H, —C₁₋₇alkyl, —C₂₋₇alkenyl, —C₂₋₇alkynyl, —C₃₋₇cycloalkyl, phenyl, benzyl, pyridinyl, pyrimidinyl, furanyl, thienyl, pyrrolyl, and a 5-, 6-, or 7-membered monocyclic non-aromatic heterocyclic ring having 1 or 2 heteroatom members selected from O, S, —N═, >NH, and >NC₁₋₄alkyl having 0, 1, or 2 double bonds; R², optionally mono- or di-substituted with R^(p), is independently selected from the group consisting of —C₁₋₇alkyl, —C₂₋₇alkenyl, —C₂₋₇alkynyl, —C₃₋₇cycloalkyl, phenyl, benzyl, pyridinyl, pyrimidinyl, furanyl, thienyl, pyrrolyl, and a 5-, 6-, or 7-membered monocyclic non-aromatic heterocyclic ring having 1 or 2 heteroatom members selected from O, S, —N═, >NH, and >NC₁₋₄alkyl, having 0, 1, or 2 double bonds; or, alternatively R¹ and R² may be taken together with the nitrogen of attachment to form a ring, said ring selected from the group consisting of: i) a 4-7 membered non-aromatic heterocyclic ring, said heterocyclic ring having 0 or 1 additional heteroatom members separated from the nitrogen of attachment by at least one carbon member and selected from O, S, —N═, >NH, and >NC₁₋₄alkyl, having 0, 1, or 2 double bonds having 0, 1, or 2 carbon members which is a carbonyl, having 0, 1, or 2 substituents R^(q); and ii) a benzo or pyrido fused 4-7 membered non-aromatic heterocyclic ring, said heterocyclic ring having 0 or 1 additional heteroatom members separated from the nitrogen of attachment by at least one carbon member and selected from O, S, —N═, >NH, and >NC₁₋₄alkyl having 0 or 1 additional double bonds having 0, 1, or 2 carbon members which is a carbonyl and having 0, 1, or 2 substituents R^(q); R^(p) is independently selected from the group consisting of —C₁₋₆alkyl, —C₂₋₆alkenyl, —C₃₋₆cycloalkyl, phenyl, pyridyl, furanyl, thienyl, benzyl, pyrimidinyl, pyrrolyl, halo, —OH, —OC₁₋₆alkyl, —C₃₋₆cycloalkyl —Ophenyl, —Obenzyl, —SH, —SC₁₋₆alkyl, —SC₃₋₆cycloalkyl, —Sphenyl, —Sbenzyl, —CN, —NO₂, —N(R^(y))R^(z) (wherein R^(y) and R^(z) are independently selected from H and C₁₋₄alkyl; or R^(y) and R^(z) may be taken together with the nitrogen of attachment to form a 5-, 6-, or 7-membered monocyclic heterocyclic ring having 1 or 2 additional heteroatom members selected from O, S, —N═, >NH, and >NC₁₋₄alkyl, said ring optionally substituted with —C₁₋₄alkyl, —OH, —OC₁₋₄alkyl, halo, or —COOC₁₋₄alkyl), —(C═O)N(R^(y))R^(z), —(C═O)C₁₋₄alkyl, —SCF₃, —OCF₃, —CF₃, and —COOC₁₋₄alkyl, and —COOH; R^(q) is independently selected from the group consisting of —C₁₋₆alkyl, halo, —OH —OC₁₋₆alkyl, —CN, —NO₂, —CF₃, and —COOC₁₋₄alkyl, R³, optionally mono- or di-substituted with R^(s), is independently selected from the group consisting of —H, —C₁₋₇alkyl, —C₂₋₇alkenyl, —C₂₋₇alkynyl, —C₃₋₇cycloalkyl, phenyl, benzyl, pyridinyl, pyrimidinyl, furanyl, thienyl, pyrrolyl, and a 5-, 6-, or 7-membered monocyclic non-aromatic heterocyclic ring having 1 or 2 heteroatom members selected from O, S, —N═, >NH, and >NC₁₋₄alkyl having 0, 1, or 2 double bonds; and R⁴, optionally mono- or di-substituted with R^(s), is independently selected from the group consisting of —C₁₋₇alkyl, —C₂₋₇alkenyl, —C₂₋₇alkynyl, —C₃₋₇cycloalkyl, phenyl, benzyl, pyridinyl, pyrimidinyl, furanyl, thienyl, pyrrolyl, and a 5-, 6-, or 7-membered monocyclic non-aromatic heterocyclic ring having 1 or 2 heteroatom members selected from O, S, —N═, >NH, and >NC₁₋₄alkyl having 0, 1, or 2 double bonds; R^(s) is independently selected from the group consisting of —C₁₋₆alkyl, —C₂₋₆alkenyl, —C₃₋₆cycloalkyl, phenyl, pyridyl, furanyl, thienyl, benzyl, pyrimidinyl, pyrrolyl, halo, —OH, —OC₁₋₆alkyl, —OC₃₋₆cycloalkyl, —Ophenyl, —Obenzyl, —SH, —SC₁₋₆alkyl, —SC₃₋₆cycloalkyl, —Sphenyl, —Sbenzyl, —CN, —NO₂, —N(R^(y))R^(z) (wherein R^(y) and R^(z) are independently selected from H and C₁₋₄alkyl; or R^(y) and R^(z) may be taken together with the nitrogen of attachment to form a 5-, 6-, or 7-membered monocyclic heterocyclic ring having 1 or 2 additional heteroatom members selected from O, S, —N═, >NH, and >NC₁₋₄alkyl, said ring optionally substituted with —C₁₋₄alkyl, —OH, —OC₁₋₄alkyl, halo, or —COOC₁₋₄alkyl), —(C═O)N(R^(y))R^(z), —(C═OC₁₋₄alkyl, —SCF₃, —OCF₃, —CF₃, —COOC₁₋₁₄alkyl, and —COOH; or, alternatively R³ and R⁴ may be taken together with the nitrogen of attachment to form a ring, said ring selected from the group consisting of: i) a 4-7 membered non-aromatic heterocyclic ring said heterocyclic ring having 0 or 1 additional heteroatom members separated from the nitrogen of attachment by at least one carbon member and selected from O, S, —N═, >NH, and >NC₁₋₄alkyl, having 0, 1, or 2 double bonds, having 0, 1, or 2 carbon members which is a carbonyl, having 0, 1, or 2 substituents R^(t); and ii) a benzo or pyrido fused 4-7 membered non-aromatic heterocyclic ring said heterocyclic ring having 0 or 1 additional heteroatom members separated from the nitrogen of attachment by at least one carbon member and selected from O, S, —N═, >NH, and >NC₁₋₄alkyl, having 0 or 1 additional double bonds, having 0, 1, or 2 carbon members which is a carbonyl and having 0, 1, or 2 substituents R^(t); R^(t) is independently selected from the group consisting of is independently selected from the group consisting of —C₁₋₆alkyl, halo, —OH, —OC₁₋₆alkyl, —CN, —NO₂, —CF₃, and —COOC₁₋₄alkyl; and enantiomers, diastereomers, hydrates, solvates and pharmaceutically acceptable salts, esters and amides thereof; and (b) administering to the subject a jointly effective amount of a histamine H₁ antagonist.
 50. A method for treating depression, mood disorders, or schizophrenia, comprising (a) administering to the subject a jointly effective amount of a compound of formula (1)

wherein in the A- and B-containing ring, I) A, B¹ and B² are CH; II) A is CH, one of B¹ and B² is N, and the other of B¹ and B² is CH; or III) A is absent B¹ is CH, and B² is O; L is —C₁₋₄alkylene- or a covalent bond; Q is —(CH₂)_(m)O—, —(CH₂)_(n)C≡C— (where the —O— and —C≡C— portions are directly attached to the ring), carbonyl or thiocarbonyl; m is 2, 3, or 4; n is 1, 2, 3, or 4; R¹, optionally mono- or di-substituted with R^(p), is independently selected from the group consisting of —H, —C₁₋₇alkyl, —C₂₋₇alkenyl, —C₂₋₇alkynyl, —C₃₋₇cycloalkyl, phenyl, benzyl, pyridinyl, pyrimidinyl, furanyl, thienyl, pyrrolyl, and a 5-, 6-, or 7-membered monocyclic non-aromatic heterocyclic ring having 1 or 2 heteroatom members selected from O, S, —N═, >NH, and >NC₁₋₄alkyl, having 0, 1, or 2 double bonds; R², optionally mono- or di-substituted with R^(p), is independently selected from the group consisting of —C₁₋₇alkyl, —C₂₋₇alkenyl, —C₂₋₇alkynyl, —C₃₋₇cycloalkyl, phenyl, benzyl, pyridinyl, pyrimidinyl, furanyl, thienyl, pyrrolyl, and a 5-, 6-, or 7-membered monocyclic non-aromatic heterocyclic ring having 1 or 2 heteroatom members selected from O, S, —N═, >NH, and >NC₁₋₄alkyl having 0, 1, or 2 double bonds; or, alternatively R¹ and R² may be taken together with the nitrogen of attachment to form a ring, said ring selected from the group consisting of: i) a 4-7 membered non-aromatic heterocyclic ring, said heterocyclic ring having 0 or 1 additional heteroatom members separated from the nitrogen of attachment by at least one carbon member and selected from O, S, —N═, >NH, and >NC₁₋₄alkyl, having 0, 1, or 2 double bonds having 0, 1, or 2 carbon members which is a carbonyl having 0, 1, or 2 substituents R^(q); and ii) a benzo or pyrido fused 4-7 membered non-aromatic heterocyclic ring, said heterocyclic ring having 0 or 1 additional heteroatom members separated from the nitrogen of attachment by at least one carbon member and selected from O, S, —N═, >NH, and >NC₁₋₄alkyl, having 0 or 1 additional double bonds, having 0, 1, or 2 carbon members which is a carbonyl, and having 0, 1, or 2 substituents R^(q); R^(p) is independently selected from the group consisting of —C₁₋₆alkyl, —C₂₋₆alkenyl, —C₃₋₆cycloalkyl, phenyl, pyridyl, furanyl, thienyl, benzyl, pyrimidinyl, pyrrolyl, halo, —OH, —OC₁₋₆alkyl, —OC₃₋₆cycloalkyl, —Ophenyl, —Obenzyl, —SH, —SC₁₋₆alkyl, —SC₃₋₆cycloalkyl, —Sphenyl, —Sbenzyl, —CN, —NO₂, —N(R^(y))R^(z) (wherein R^(y) and R^(z) are independently selected from H and C₁₋₄alkyl; or R^(y) and R^(z) may be taken together with the nitrogen of attachment to form a 5-, 6-, or 7-membered monocyclic heterocyclic ring having 1 or 2 additional heteroatom members selected from O, S, —N═, >NH, and >NC₁₋₄alkyl, said ring optionally substituted with —C₁₋₄alkyl, —OH, —OC₁₋₄alkyl, halo, or —COOC₁₋₄alkyl), —(C═O)N(R^(y))R^(z), —(C═O)C₁₋₄alkyl, —SCF₃, —OCF₃, —CF₃, and —COOC₁₋₄alkyl, and —COOH; R^(q) is independently selected from the group consisting of —C₁₋₆alkyl, halo, —OH, —OC₁₋₆alkyl, —CN, —NO₂, —CF₃, and —COOC₁₋₄alkyl, R³, optionally mono- or di-substituted with R^(s), is independently selected from the group consisting of —H, —C₁₋₇alkyl, —C₂₋₇alkenyl, —C₂₋₇alkynyl, —C₃₋₇cycloalkyl, phenyl, benzyl, pyridinyl, pyrimidinyl, furanyl, thienyl, pyrrolyl, and a 5-, 6-, or 7-membered monocyclic non-aromatic heterocyclic ring having 1 or 2 heteroatom members selected from O, S, —N═, >NH, and >NC₁₋₄alkyl, having 0, 1, or 2 double bonds; and R⁴, optionally mono- or di-substituted with R^(s), is independently selected from the group consisting of —C₁₋₇alkyl, —C₂₋₇alkenyl, —C₂₋₇alkynyl, —C₃₋₇cycloalkyl, phenyl, benzyl, pyridinyl, pyrimidinyl, furanyl, thienyl, pyrrolyl, and a 5-, 6-, or 7-membered monocyclic non-aromatic heterocyclic ring having 1 or 2 heteroatom members selected from O, S, —N═, >NH, and >NC₁₋₄alkyl, having 0, 1, or 2 double bonds; R^(s) is independently selected from the group consisting of —C₁₋₆alkyl, —C₂₋₆alkenyl, —C₃₋₆cycloalkyl, phenyl, pyridyl, furanyl, thienyl, benzyl, pyrimidinyl, pyrrolyl, halo, —OH, —OC₁₋₆alkyl, —OC₃₋₆cycloalkyl, —Ophenyl, —Obenzyl, —SH, —SC₁₋₆alkyl, —SC₃₋₆cycloalkyl, —Sphenyl, —Sbenzyl, —CN, —NO₂, —N(R^(y))R^(z) (wherein R^(y) and R^(z) are independently selected from H and C₁₋₄alkyl; or R^(y) and R^(z) may be taken together with the nitrogen of attachment to form a 5-, 6-, or 7-membered monocyclic heterocyclic ring having 1 or 2 additional heteroatom members selected from O, S, —N═, >NH, and >NC₁₋₄alkyl, said ring optionally substituted with —C₁₋₄alkyl, —OH, —OC₁₋₄alkyl, halo, or —COOC₁₋₄alkyl), —(C═O)N(R^(y))R^(z), —(C═O)CO₁₋₄alkyl, —SCF₃, —OCF₃, —CF₃, —COOC₁₋₄alkyl, and —COOH; or, alternatively R³ and R⁴ may be taken together with the nitrogen of attachment to form a ring, said ring selected from the group consisting of: i) a 4-7 membered non-aromatic heterocyclic ring said heterocyclic ring having 0 or 1 additional heteroatom members separated from the nitrogen of attachment by at least one carbon member and selected from O, S, —N═, >NH, and >NH, and >NC₁₋₄alkyl, having 0, 1, or 2 double bonds having 0, 1, or 2 carbon members which is a carbonyl, having 0, 1, or 2 substituents R^(t); and ii) a benzo or pyrido fused 4-7 membered non-aromatic heterocyclic ring said heterocyclic ring having 0 or 1 additional heteroatom members separated from the nitrogen of attachment by at least one carbon member and selected from O, S, —N═, >NH, and >NC₁₋₄alkyl having 0 or 1 additional double bonds, having 0, 1, or 2 carbon members which is a carbonyl, and having 0, 1, or 2 substituents R^(t): R^(t) is independently selected from the group consisting of is independently selected from the group consisting of —C₁₋₆alkyl, halo, —OH, —OC₁₋₆alkyl, —CN, —NO₂, —CF₃, and —COOC₁₋₄alkyl; and enantiomers, diastereomers, hydrates, solvates and pharmaceutically acceptable salts, esters and amides thereof; and (b) administering to the subject a jointly effective amount of a selective serotonin re-uptake inhibitor.
 51. A method for treating narcolepsy, excessive daytime sleepiness (EDS), Alzheimer's disease, depression, attention deficit disorders, MS-related fatigue, post-anesthesia grogginess, cognitive impairment, schizophrenia, spasticity associated with cerebral palsy, age-related memory decline, idiopathic somnolence, or jet-lag, comprising (a) administering to the subject a jointly effective amount of a compound of formula (1)

wherein in the A- and B-containing ring I) A, B¹ and B² are CH; II) A is CH, one of B¹ and B² is N, and the other of B¹ and B² is CH; or III) A is absent B¹ is CH, and B² is O; L is —C₁₋₄alkylene- or a covalent bond; O is —(CH₂)_(m)O—, —(CH₂)_(n)C≡C— (where the —O— and —C≡C— portions are directly attached to the ring) carbonyl or thiocarbonyl; m is 2, 3, or 4; n is 1, 2, 3, or 4; R¹, optionally mono- or di-substituted with R^(p), is independently selected from the group consisting of —H, —C₁₋₇alkyl, —C₂₋₇alkenyl, —C₂₋₇alkynyl, —C₃₋₇cycloalkyl, phenyl, benzyl, pyridinyl, pyrimidinyl, furanyl, thienyl, pyrrolyl, and a 5-, 6-, or 7-membered monocyclic non-aromatic heterocyclic ring having 1 or 2 heteroatom members selected from O, S, —N═, >NH, and >NC₁₋₄alkyl, having 0, 1, or 2 double bonds; R², optionally mono- or di-substituted with R^(p), is independently selected from the group consisting of —C₁₋₇alkyl, —C₂₋₇alkenyl, —C₂₋₇alkynyl, —C₃₋₇cycloalkyl, phenyl, benzyl, pyridinyl, pyrimidinyl, furanyl, thienyl, pyrrolyl, and a 5-, 6-, or 7-membered monocyclic non-aromatic heterocyclic ring having 1 or 2 heteroatom members selected from O, S, —N═, >NH, and >NC₁₋₄alkyl, having 0, 1, or 2 double bonds; or, alternatively R¹ and R² may be taken together with the nitrogen of attachment to form a ring, said ring selected from the group consisting of: i) a 4-7 membered non-aromatic heterocyclic ring, said heterocyclic ring having 0 or 1 additional heteroatom members separated from the nitrogen of attachment by at least one carbon member and selected from O, S, —N═, >NH, and >NC₁₋₄alkyl, having 0, 1, or 2 double bonds having 0, 1, or 2 carbon members which is a carbonyl having 0, 1, or 2 substituents R^(q); and ii) a benzo or pyrido fused 4-7 membered non-aromatic heterocyclic ring, said heterocyclic ring having 0 or 1 additional heteroatom members separated from the nitrogen of attachment by at least one carbon member and selected from O, S, —N═, >NH, and >NC₁₋₄alkyl, having 0 or 1 additional double bonds having 0, 1, or 2 carbon members which is a carbonyl and having 0, 1, or 2 substituents R^(q); R^(p) is independently selected from the group consisting of —C₁₋₆alkyl, —C₂₋₆alkenyl, —C₃₋₆cycloalkyl, phenyl, pyridyl, furanyl, thienyl, benzyl, pyrimidinyl, pyrrolyl, halo, —OH, —OC₁₋₆alkyl, —OC₃₋₆cycloalkyl, —Ophenyl, —Obenzyl, —SH, —SC₁₋₆alkyl, —SC₃₋₆cycloalkyl, —Sphenyl, —Sbenzyl, —CN, —NO₂, —N(R^(y))R^(z) (wherein R^(y) and R^(z) are independently selected from H and C₁₋₄alkyl; or R^(y) and R^(z) may be taken together with the nitrogen of attachment to form a 5-, 6-, or 7-membered monocyclic heterocyclic ring having 1 or 2 additional heteroatom members selected from O, S, —N═, >NH, and >NC₁₋₄alkyl, said ring optionally substituted with —C₁₋₄alkyl, —OH, —OC₁₋₄alkyl, halo, or —COOC₁₋₄alkyl), —(C═O)N(R^(y))R^(z), —(C═O)C₁₋₄alkyl, —SCF₃, —OCF₃, —CF₃, and —COOC₁₋₄alkyl, and —COOH; R^(q) is independently selected from the group consisting of —C₁₋₆alkyl, halo, —OH, —OC₁₋₆alkyl, —CN, —NO₂, —CF₃, and —COOC₁₋₄alkyl, R³, optionally mono- or di-substituted with R^(s), is independently selected from the group consisting of —H, —C₁₋₇alkyl, —C₂₋₇alkenyl, —C₂₋₇alkynyl, —C₃₋₇cycloalkyl, phenyl, benzyl, pyridinyl, pyrimidinyl, furanyl, thienyl, pyrrolyl, and a 5-, 6-, or 7-membered monocyclic non-aromatic heterocyclic ring having 1 or 2 heteroatom members selected from O, S, —N═, >NH, and >NC₁₋₄alkyl, having 0, 1, or 2 double bonds; and R⁴, optionally mono- or di-substituted with R^(s), is independently selected from the group consisting of —C₁₋₇alkyl, —C₂₋₇alkenyl, —C₂₋₇alkynyl, —C₃₋₇cycloalkyl, phenyl, benzyl, pyridinyl, pyrimidinyl, furanyl, thienyl, pyrrolyl, and a 5-, 6-, or 7-membered monocyclic non-aromatic heterocyclic ring having 1 or 2 heteroatom members selected from O, S, —N═, >NH, and >NC₁₋₄alkyl, having 0, 1, or 2 double bonds; R^(s) is independently selected from the group consisting of —C₁₋₆alkyl, —C₂₋₆alkenyl, —C₃₋₆cycloalkyl, phenyl, pyridyl, furanyl, thienyl, benzyl, pyrimidinyl, pyrrolyl, halo, —OH, —OC₁₋₆alkyl, —OC₃₋₆cycloalkyl, —Ophenyl, —Obenzyl, —SH, —SC₁₋₆alkyl, —SC₃₋₆cycloalkyl, —Sphenyl, —Sbenzyl, —CN, —NO₂, —N(R^(y))R^(z) (wherein R^(y) and R^(z) are independently selected from H and C₁₋₄alkyl; or R^(y) and R^(z) may be taken together with the nitrogen of attachment to form a 5-, 6-, or 7-membered monocyclic heterocyclic ring having 1 or 2 additional heteroatom members selected from O, S, —N═, >NH, and >NC₁₋₄alkyl, said ring optionally substituted with —C₁₋₄alkyl, —OH, —OC₁₋₄alkyl, halo, or —COOC₁₋₄alkyl), —(C═O)N(R^(y))R^(z), —(C═O)C₁₋₄alkyl, —SCF₃, —OFC₃, —CF₃, —COOC₁₋₄alkyl, and —COOH; or, alternatively R³ and R⁴ may be taken together with the nitrogen of attachment to form a ring, said ring selected from the group consisting of: i) a 4-7 membered non-aromatic heterocyclic ring said heterocyclic ring having 0 or 1 additional heteroatom members separated from the nitrogen of attachment by at least one carbon member and selected from O, S, —N═, >NH, and >NC₁₋₄alkyl, having 0, 1, or 2 double bonds having 0, 1, or 2 carbon members which is a carbonyl having 0, 1, or 2 substituents R^(t); and ii) a benzo or pyrido fused 4-7 membered non-aromatic heterocyclic ring said heterocyclic ring having 0 or 1 additional heteroatom members separated from the nitrogen of attachment by at least one carbon member and selected from O, S, —N═, >NH, and >NC₁₋₄alkyl, having 0 or 1 additional double bonds having 0, 1, or 2 carbon members which is a carbonyl and having 0, 1, or 2 substituents R^(t); R^(t) is independently selected from the group consisting of is independently selected from the group consisting of —C₁₋₆alkyl, halo, —OH, —OC₁₋₆alkyl, —CF₃, and —COOC₁₋₄alkyl; and enantiomers, diastereomers, hydrates, solvates and pharmaceutically acceptable salts, esters and amides thereof; and (b) administering to the subject a jointly effective amount of modafinil. 